Biological Memory

What We Know and Where We Are Going
Written by
Akara Metasuk
A Handbook for the Ph.D. Qualifying Examination in Neuroscience Research Center for Neuroscience | Institute of Molecular Biosciences | Mahidol University
23 August 2012
Table of Contents
Page Introduction to Biological Memory Chapter 1 | History of the Study of Memory Chapter 2 | Classification of Memory and the Processing Chapter 3 | Gross Structure of the Brain Involved in Memory Processing Chapter 4 | Cellular and Molecular Structure of the Brain Involved in Memory Processing Chapter 5 | Brain Development and Memory Functions during Brain Development Chapter 6 | Neurotransmitting Chemicals Known to be Related to Memory Processing Chapter 7 | Hormonal Regulations of Memory Chapter 8 | Effects of Cellular Changes to Memory; Neuronal Plasticity and Apoptosis Chapter 9 | Neuropathology/Psychiatry of Memory and Brain Aging Chapter 10 | Drug Addiction and Memory 1 5 12 24 32 46 57 70 81 97 110
Chapter 11 | Medicines, Chemicals and Activities for Memory Booster, Memory Alteration and Memory Clearance 119 Chapter 12 | Models and Algorithms for the Study of Memory and Cognitive Neural Prosthesis Forthcoming Studies Acknowledgement 132 A B
Qualifying Exam in Neurosciences
Akara Metasuk
RCN, Mahidol University, Thailand
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Introduction to Biological Memory

Akara Metasuk Memory is one of the most astounding abilities that human beings developed and won the race out of other organisms. Every day, from supermarkets to hypermarkets, we can find a lot of products that promise to boost the ability of memory processing. It signifies that memory will become the subject of mass interest in the near future. Unfortunately, it is still unclear what the object in memory is, though scientists and researchers have logically studied and added more knowledge to memory via decades of various learning tasks studied in animals. More details about the history of the studies will be given in chapter 1. Memory (/mm()ri/, noun, plural memories) The faculty by which the mind stores and remembers information. Oxford online dictionary, accessed in January 2012. The meaning of memory from the dictionary, shown above, may not be accurate enough for scientists who study memory since there is no such complete criterion to judge whether a person remembers information, and also it is still in debate what the mind is. On the other hand, scientists interpret memory as the ability of an organism to store, retain, and recall information. This means that to define a thing as a memory, it must be encoded (stored), kept for a period of biological time frame (retained), and retrieved (recalled) by the organism. These are the 3 processes that scientists classify memories into many different types, which I will give more detail in chapter 2. Behavioral studies of animals learning various types of tasks let scientists consider later where or what areas in the brain that are involved in memory functions. To the fact that scientists divide memories into many types, they found that some areas in the brain may serve for only a few types of memory, while the other areas do not. However, this doesnt
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mean that losing one area in the brain will always lead to the lost of functions in every kinds of memory, since one area that serves for the function of one memory may not be significant for the function of the other. In chapter 3, gross structure of the brain will be dissected literally to show the areas which are essential for each types of memory. The cellular structure and mechanisms involved in memory is another area of research which has been extensively studied in late 20th century, after the gross structure of the brain is clearly understood. This will be the focus of Chapter 4. Later in Chapter 5, the developmental studies of the brain will be discussed about how scientists unveil the facts about critical periods of sensations and memory. This is a very important field when some of the abilities are impossible to regenerate or can be hardly restored if the children havent been trained correctly before the learning windows are closed. Although genetics is the main factor that has effects to brain functions, epigenetic factors, especially which accepted during childhood, are the other factors that have inevitable effects to memory functions in later ages to adulthood. Having discussed about developmental aspects on memory functions, in Chapter 6 I will move on to a deeper area to look into how neuro-chemicals, or neurotransmitters diverse within the brain. As scientists know that each brain areas have different main neurotransmitter receptors dispersed in the structure, and each neurotransmitters play different roles to the function of the brain. It is important to be clear about how neurotransmitters have effects to memory, or what types of neurotransmitter the memory is dependent to. The understanding in this topic will provide the basic information for the following chapters which will give details about how memory can be manipulated. The first memory modulator to be focused in Chapter 7 is hormone. Memory mediators can be
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modulated by a lot of hormonal controls which follow the changes in mood, stress, menstrual cycle, and medicine. Apart from chemical changes that have acute to chronic effects to memory functions, vast changes in cellular structure, whether the degeneration or the plasticity of neuron, can have major changes which may develop to neurodegenerative diseases. Chapter 8 will focus on the cellular structural changes of neurons and how they can affect the function of memory. To exemplify this, it would be neuronal apoptosis and neuronal plasticity. Neurodegenerative diseases and their pathology will also be discussed in Chapter 9. There, the structural changes of the brain will reveal how different areas of the brain work together for memory processing. Some evidence suggested that the gross structural changes of the brain may develop from inappropriate life styles of the patient early in their life. One most studied behavior of those patients is drug addiction. To draw a relationship how memory functions can be affected by drug addiction, the effects of drug chemicals to the brain is needed to be understood clearly. In Chapter 10, I will focus on how chemicals in the drugs modulate the cellular structure of the brain in acute phase. The chronic effects of drug addiction will also be discussed how they irreversibly modify the structure of the brain and give rise to neurodegenerative diseases. Because the functions of the brain is basically dependent on the chemical homeostasis in cellular structure, the manipulation of memory functions are thought to be tangibly managed by the effects of the changes in chemical activities. Medicines are given to patients in neurodegenerative diseases to fade, but may not change the structure of, the symptoms. Not only to neurodegenerative patients, normal people are also seeking for medicines to boost their memory functions since memory is one of the standards people
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believe to reflect their cognitive ability. On the other hand, too much memory may become a problem to some people who suffer from bad experiences. Post-traumatic stress disorder and anxiety are the disorders that the patients wish their bad experience or memory is removed. Memory booster, memory alteration and memory clearance medicines are the focus of Chapter 11. Physical activities that manipulate brain chemicals will also be discussed together. Advances in Neurosciences gave more information about answering how memory works, and one day scientists may finally point out the way to completely control human memory. However, the understanding of the brain only in biological field may not answer all of the questions. In Chapter 12, memory models and algorithms developed by engineers will be discussed how they can explain the processes of memory. An example for this can be the case of cognitive neural prosthesis. Scientists in this area averted from the question what memory is to answer the question how memory can be completely controlled. Finally, their discoveries may help answer the question about what the object of memory is in the end. The articles in this writing are provided for the qualifying examination Biological Memory: What We Know and Where We Are Going arranged by The Research Center for neuroscience during my Ph.D. program in Neurosciences at Mahidol University. All of the major fields of Neurosciences are taken to the discussion while the main focus is on memory, which is my field of interest. Due to the active discoveries in Neurosciences, this writing may become outdated in a few years. More discussions on the topics in any articles in this writing are always kindly accepted. Please always feel free to contact me at nodrightnow@hotmail.com.
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History of the Study of Memory
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Chapter 1 History of the Study of Memory

Akara Metasuk Before the study of the brain, the concept of mind has been discussed by various groups of philosophers. Mind is sometimes tied to the concept of thinking such that we say I have nothing on my mind. meaning we dont have any idea or any thinking. Dualism and Monism were developed early in history to explain how the mind works. Later, these concepts come to a great debate called the mind-body problem among philosophers and scientists. Perspectives of mind in religious views are also diverse, and they grew their roots on people in different continents. Mind, once was an untouchable concept may have become a concrete object such that can be explained by todays neuroscientists. However, there may remain some problems to be solved since Quantum Mechanics play an overlapping concept about the mind too. Monism explains that everything in the universe is held by unity. This is the main concept of Brahman ( ) in Hinduism and the emptiness of the nature of the world in Buddhism. In epistemological idealism, it is believed that all is in and of the mind, meaning that man is God since God is also in the mind. Monism concept can be divided to Idealism, Neutralism, and Physicalism. Idealism Monism concept is focused to the mind. Only the mind is real. Unlike Physicalism which believes that only the physical is real. The mind can be reduced to the physical. On the other hand, Neutral Monism made up a new substance which holds the mind and the physical together. This substance can be energy or another unknown object. According to the branches of Monism, Physicalism may be the idea that is closest in meaning to the discoveries in sciences today which will be discussed later in this chapter.
Qualifying Exam in Neurosciences Akara Metasuk RCN, Mahidol University, Thailand
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All kinds of Monism are contradictory to the belief about spirituality, which is the root of Dualism. Dualism, which holds belief about the existence of two different objects, not one, is a basis in religions and sciences too. It explains religious views about good and evil, moral and immoral. It also extends in Chinese philosophy and expresses basically as the principles of Yin and Yang, female and male, dark and light, or passive and active in Taoism and Confucianism. The existence of Dualism usually discuss about the existence of two different objects as the key of equilibrium homeostasis. As science developed, Dualism also takes its steps in explaining how the mind works. Atomistic Buddhism believes about the Dualism between the nonphysical consciousness and the nonphysical atom. Please note that the Dualism in Buddhism is very close to the belief in western philosophy that separate the mind, or the consciousness, from the brain, or the atom. The big difference is that the atom in Atomistic Buddhism is also energy, nonphysical. In early periods of the philosophy of mind, Dualism is between the nonphysical mind and the physical body, so-called the mind-body Dualism. The argument about mind-body plays a significant role in the understanding of how the brain works. The mind-body problem is set between two major believes, Dualism and Monism. Dualisms question is about how the physical cells or electrochemical process can trigger consciousness. Ren Descartes may be the first who stated mind-body Dualism in an organized way in 1641.(1) He distinguished the mind from the brain, and considered the brain as only the seat of intelligence. Dualism states that the mind which represents the self is the soul, not the brain. Unlike Dualism, Monism does not divide the concept into two. Physicalistic Monism is the most talked-about one. It says that the only substance is physical which can be experimented in science. As a scientist, what cannot be proven of existence cannot be said that it exists, but it doesnt mean that it isnt there either. Like the non-physical soul, its existence is not proven in science, but that doesnt mean it doesnt exist. This problem is still
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kept for further discoveries, but before that, scientists have associated many aspects of the brain that is devoted for the mind. If we change the brain, we change the mind. If we destroy the brain, we destroy the mind. It is no doubt that the brain is important for the functions of the mind, consciousness, and learning. Have been stated in the introduction that memory is the ability of an organism to encode, store, and recall information, this can be the building block for learning. Learning is a change in an organisms behavior which occurs because of the external stimuli, usually by acquiring information, but not by chemicals or drugs. Learning cannot occur if the organism cannot encode or recall the information. Thats why memory is one basic abilities the organism need to have for their learning. Disabilities of learning may be a normal issue in some children, but these children may develop their disabilities because they are deflecting in different processes of memory. This will be the core concept in the next chapter. In addition, learning is usually studied together with memory in the field that these two words are often used together as learning and memory. Scientists have studied behaviors and learning processes of animals for decades, and they have categorized learning by the complexity of the process; basically non-associative learning, which can be found from lower invertebrates to vertebrates, and associative learning, which is the core value of higher animals and human beings. In basic, habituation and sensitization are the two opposite learning patterns in nonassociative learning. Habituation is the learning that the behavioral response is decreasing with the time of stimulus repetition. The stimuli can be rewarding or harmful to the animal. An example for this can be a bird and a passer-by. At first, the bird may fly away from the passer-by because it perceive human as a harmful stimulus. If the passer-by does not harm the bird, then later the bird will decrease its response and finally stop flying away. This also
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applies when the bird is presented with some food in a closed box. If the bird cannot eat the food, finally it will not pay attention to the food in that box. Habituation is basic in animals and some protozoan. Another type of non-associative learning is sensitization. Organisms respond more dramatically with the time of external stimulation. This can be explained by a passer-by that walks to a group of birds. At first, the birds may not feel scared of the man and just enjoy their food. If the man continue walking into the birds or act offensively, the flock of birds may fly away, and finally, if repeated, they will never get along with the passerby. Another example can be the sensitization that occurs in the peripheral nerves of human when we rub our arms. At first it can be warm, but later it turns to pain. While habituation and sensitization is seen basic in animals, associative learning can be found only in higher animals. This kind of learning requires the association between two stimuli or behaviors, and that needs more complex neuronal connection. The first studied associative learning is imprinting. Imprinting is when the characteristics of one stimulus are associated with the other stimuli. The association usually occur rapidly particularly after birth or at a particular age. It was studied extensively by Konrad Lorenz who worked with geese.(2) He found that the new-born geese could imprint the first moving stimulus they saw in 13-16 hours after hatching. He called this period the critical period for imprinting. Imprinting is also the basic explanation for sexual fetishism in the way that organisms learn the characteristics of their mates or become sexually attracted to particular objects or situations. Westermarck effect can also be explained by imprinting. It happens to two people who live in proximity. This can result as being sexual attracted to each other. Classical conditioning or Pavlovian conditioning is another associative learning that associates two unrelated stimuli. It was demonstrated by Ivan Pavlov in 1927.(3-4) Natural response (Unconditional response - UR) can be collected when an organism receives an
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unconditional stimulus (US), and no UR should be seen with a neutral stimulus. When an US is presented repeatedly along with the neutral stimulus, the organism may associate the US and the neutral stimulus and later can have a response to neutral stimulus just like how it responds to the US. This is the conditional response (CR) and the neutral stimulus now becomes a conditional stimulus (CS). Classical conditioning may be done in two ways; the forward conditioning and the backward conditioning. Forward conditioning is the process of associational learning that the US is paired with the CS, and the CS is presented before the US. If the learning occurs, the animal will have a CR for the CS. Backward conditioning is in reverse, the US is paired with the CS, but the CS is presented after the US. The response of the organism to backward conditioning is different from forward conditioning. The presence of the CS will inhibit the response instead of triggering it. Operant conditioning is another associative learning very similar to classical conditioning. It uses reinforcement of punishment to associate the animals action and a stimulus. It differs from classical conditioning in the way that classical conditioning associates two stimuli, not a stimulus with the animals action. The example for the reinforcement Operant conditioning is the Skinner box with a feeding bar. An organism may learn by associating the action of knocking the bar and the food stimulus. The reinforcement can be positive or negative. Positive reinforcement occurs when a reward is presented after the animals action. Negative reinforcement is when a removal of aversive stimulus is done after the animals action. In contrast to reinforcement Operant conditioning, a box with water-splashing rooms may generate punishment Operant conditioning in the way that the organism learns not to enter the water-splashing rooms. Knowing how the brain works in behavioral aspects, scientists have tried to uncover how the memory is processed in cellular level. It was proposed by Santiago Ramn y Cajal
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that the mechanism of learning do not require the formation of new neurons.(5) Donald Hebb, in 1949,(6) supported this idea by introducing Hebbian theory which stated that cells may grow new connections to enhance the ability to communicate which is summarized by Carla Shatz as Cells that fire together, wire together.(7) Gene expression and chemical signaling are the basic building blocks for the understanding of how neurons communicate. After the discovery of cAMP response element-binding protein (CREB) in 1987(8), the pathways of chemical messaging in neurons were drawn to almost completion by Eric Richard Kandel in 2000(9-10). His discoveries also support the Hebbian theory. The study of memory and the mind is not limited to only biological fields but also extends to quantum mechanics. The quantum mind is a hypothesis that uses quantum mechanical phenomena to explain the states of brain functions. Roger Penrose and Stuart Hameroff in 1931 stated a theory, Orchestrated Objective Reduction (Orch-OR), that assumes the consciousness is from the brain.(11) Mathematics is the tool they used for considering the computation of synaptic communication of neurons. In 1960, Hiroomi Umezawa and Herbert Frhlich introduced Quantum Brain Dynamics theory (QBD) to relate water molecules to the function of the brain.(12) Since the brain is 70% water, it is possible that water molecules generate quantum field or the cortical field for the brain. The cortical field interacts with neurons. The molecular waves are proposed to be the driving force for ATP, the activities of ion channels, and the synaptic signaling.
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References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. REN DESCARTES. 2002 [updated 2002 9 December 2002; cited 2012 18 July]; Available from: http://renedescartes.com. Foundation TN. Konrad Lorenz - Autobiography1973 [cited 2012 18 July]: Available from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1973/lorenz.html. Ivan Patrovich Pavlov. 2003 [updated 2003 14 April 2003; cited 2012 18 July]; Available from: http://www.ivanpavlov.com/. Foundation TN. Ivan Pavlov - Biography1904 [cited 2012 18 July]: Available from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1904/pavlov-bio.html/. Foundation TN. Santiago Ramn y Cajal - Biography1906 [cited 2012 18 July]: Available from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1906/cajal-bio.html. Psychology TGC. Dr. Donald Hebb. 2005-2008. Thomas P. Brainy Women. Harvard Magazine. 2002:46-86. Montminy MR, Bilezikjian LM. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987;328(6126):175-8. Barco A, Bailey CH, Kandel ER. Common molecular mechanisms in explicit and implicit memory. J Neurochem. 2006;97(6):1520-33. Hawkins RD, Kandel ER, Bailey CH. Molecular mechanisms of memory storage in Aplysia. Biol Bull. 2006;210(3):174-91. Stuart Hameroff RP. Orchestrated Objective Reduction of Quantum Coherence in Brain Microtubules: The "Orch OR" Model for Consciousness1996 [cited 2012 18 July]: Available from: http://www.quantumconsciousness.org/penrose-hameroff/orchor.html. Mind Q. Quantum Brain Dynamics2012 [cited 2012 18 July]: Available from: http://www.quantum-mind.co.uk/qbd-1-c57.html.
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Classification of Memory and the Processing
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Chapter 2 Classification of Memory and the Processing

Akara Metasuk The brain is not homogeneous, and the processing of memory can vary in different areas. Scientists have set categories for memory by some criteria such as the characteristics of the information and the temporal variables. The types of memory are almost the products of the hypotheses of memory models. The most popular model in neuroscience may be the multi-store model proposed by Atkinson and Shiffrin in 1968.(1-2) They stated that human memory can be processed in a sequence of three types of memory; sensory memory, short-term memory, and long-term memory. The other model was proposed by Baddeley in 1974, the working memory model.(3-4) It expands the understanding of the short-term storage of memory in Atkinson-Shiffrin model. Three main concepts were the core of Baddeley working memory model; the central executive, the phonological loop, and the visuospatial sketchpad. Later he added another concept, episodic buffer, to his model. In Atkinson-Shiffrin multi-store memory model, memory is processed first as the sensory memory then it is stored in short-term memory and long-term memory, respectively. Sensory memory is collected by sensory receptors and stored in the nervous system. This includes the sense of sight, taste, smell, hearing, and touch. This type of memory is perceived unconsciously. It cannot be controlled by attention. It collects high resolution of information; for example the iconic memory can store visual information for about 12 items at a time, but the memory is stored in very short period of time at about 200 500 milliseconds. Short term memory decayed fast and become replaced by new memory. Rehearsal cannot prolong this kind of memory too. The role of sensory memory is to provide the details of the
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sensory experience which can be processed by working memory for producing a short-term memory. Sensory memory can be subcategorized into iconic memory, echoic memory, and haptic memory. Iconic memory provides the visual perception and can last no more than 100 milliseconds according to the study by Johann Andreas Segner in 1740.(5) The pathway for the memory is drawn from the photoreceptor cells of the retina to the occipital lobe of the brain. Echoic memory represents the auditory sense form the hair cells in the ears to the temporal lobe of the brain. Haptic memory is for the tactile sense of pressure and pain. The information is sent from anywhere on the skin to the spinal cord and finally to the postcentral gyrus of the parietal lobe of the brain. Short-term memory is held in an active state of consciousness for a short period of less than a minute without rehearsal. It stores less definition of information than the sensory memory. The amount of information is also limited, for example, it is proposed that the capacity of remembering elements is only 5-9 items (7 2) in The Magical Number Seven published by George Armitage Miller in 1956.(6) The storage of short-term memory and the fading of memory can be the result of neurotransmitter depletion. As neurons fire, neurotransmitters are released to synaptic clefts. After that, the degradation and the reuptake of neurotransmitters may be the functions that decay the short-term memory. Sensory memory is sometimes confused to be called a working memory. Accordingly, the sensory memory is not exactly the working memory, but it can be explained by the structure of working memory. (Figure 2.1) Sensory memory is one type of memory, but working memory is a concept to describe how memory system works. Short-term memory is under the control of consciousness, and the capacity of ones short-term memory can vary depending on the amount of attention. The main cortical structures which are
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required for short-term memory are the prefrontal cortex and the parietal multimodal sensory area. Factors that can affect this type of memory can be the interference that distracts attention. One effective technique to improve short-term memory can be chunking. This is how the items to remember are processed into groups. People usually have the capacity of remembering three chunks in one time. This also is the basic explanation for remembering telephone numbers in chunks. Long-term memory is the last part of the multi-store memory model. It becomes stronger with time after the perception. The best factor that strengthens long-term memory is rehearsal. If the memory is stored in short-term for long time, it has tendency to become long-term memory. The storage of long-term memory is under discoveries, but it is believed that the underlying mechanism is the transfer of short-term memory to the other storage area for long-term. This is understood to be the result of long-term potentiation and long-term depression which will be discussed in chapter 4. Recall of memory in appropriate time can make long-term memory to last for a life time. One of the processes that may shape longterm memory is sleep, especially during rapid-eye movement (REM) and slow-wave sleep (SWS).(7) The procedural memory and the declarative memory are benefited from REM and SWS, respectively. Long-term memory can be separated into two categories by using the characteristics of the information as the criteria. They are explicit memory and implicit memory. Explicit memory is sometimes called the declarative memory, but actually these two concepts are not the same. Explicit memory is the memory that has to be recalled consciously. This involves declarative memory and emotional memory. Emotional memory stores information about events that evoke emotional response. The main brain areas for emotional memory are the amygdala and the prefrontal cortex. The information about the
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emotional memory cannot be explained by the person who holds the memory. This forms a contrast to declarative memory, which can be transferred from one person to the others by telling. The two kinds of declarative memory are semantic memory and episodic memory. Semantic memory is the memory which is not related to specific contexts. It is the basic memory for general knowledge and understandings, such as The world is round and Birds have wings. It is still controversial where in the brain semantic memory is stored. One view is that it is processed in the brain areas where are important for episodic memory, including the medial temporal lobes and the hippocampal formation. It was suggested that the hippocampal formation; the hippocampus, the entorhinal cortex, and the perirhinal cortex, is involved in the formation of semantic memory in the cortex. However, some scientists stated that the hippocampus is only an important structure for episodic memory and spatial cognition. The site of semantic memory storage may be in the temporal neocortex or throughout the brain. It is possible that the storage of semantic memory depends on the type of modality. Semantic memory about sound can be stored in the temporal lobe, visual knowledge about appearance of things may be stored in the visual cortex, and so on. In addition, the temporal poles were suggested to be the zone for multimodal representation of semantic memory, since any damage to these areas can cause semantic dementia. Episodic memory is similar to semantic memory only in the way that it can be recalled consciously. Compared to semantic memory, episodic memory is more about autobiographical events, not general knowledge. It is usually tied to times, places, emotions, and any possible contexts, as described by Endel Tulving, and thats also the reason why emotion effectively increase the chance of remembering an episodic memory.(8) It also includes flashbulb memories or the basic events which is critical for only some social
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groups. Tulving drew a relationship line between semantic memory and episodic memory. He stated that semantic memory can be derived from a collection of episodic memory. Episodic memories can form a map and shape the information in semantic memory; therefore, semantic memory can easily be affected by the defects in episodic memory. The main area of the brain proposed to be the area for the formation of episodic memory is the medial temporal lobe and the hippocampus, just like semantic memory. One big difference may be that the prefrontal cortex has been added for its essential role in the organization of the information and strengthens the information about time and place for episodic memory. Apart from the explicit memory, theres another kind of memory which forms the general behavior and identities of human unconsciously. It is the implicit memory or the nondeclarative memory. (Also note that emotional memory is also a non-declarative memory but an explicit memory.) Implicit memory guides an organism to perform actions. It is unconsciously controlled. It is the basis of the illusion-of-truth effect when people tend to accept something a truth if they feel familiar about the story. The other type of implicit memory that we share everyday is procedural memory, which aids people how to do things. Procedural learning is the reason why people dance better or draw pictures more precisely by practicing. The brain areas involved in procedural memory are the striatum, basal ganglia, cerebellum, and limbic system. The dorsolateral striatum controls the movement by two diverging pathways that counteract each other. It also forms cortex-basal ganglia-thalamus-cortex loop for controlling the motor skill. Cerebellum works by fine-tuning motor movement, and it is also suggested that the cerebellum is the place for procedural memory storage. Memory can also be categorized by the temporal aspects of the information. Retrospective memory is the memory about the information in the past. Mental time travel
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(MTT) is an ability of an organism to imagine about the past experience or the incoming events.(9) Retrospective memory also explains how MTT happens. Retrospective memory can be implicit or explicit, and the brain areas involved in retrospective memory depends on the type of information they manage. On the other hand, prospective memory, which refers to memory of remembering to do an action in the future, is all about the episodic memory. Prospective memory can be classified into event-based memory, the memory about remembering to do an action in a certain situation such as when seeing a particular object, and time-based memory, the memory about remembering to do an action in a certain point of time. Because prospective memory needs information from episodic memory and retrospective memory, it becomes controlled by the frontal lobe to fulfill intention. The parietal lobe and the limbic system are also important since they are the general blocks for episodic memory. In multi-store memory model, memory can be transformed from one to another, for example from short-term memory to long-term memory, but the model did not explain how the information is manipulated. Baddeley and Hitch, in 1974, finally described this missing concept by their working memory model. In 2000, they concluded that the working memory model consists of one main component, the central executive, and three slave systems; the phonological loop, the visuo-spatial sketch pad, and the episodic buffer. (Figure 2.1) The main component, the central executive, is the component that controls and regulates the cognitive process. It combines different information together, coordinates the slave systems, and is the laying point of its function for attention and inhibition. The central executive is required for any tasks, but will become critical in multiple tasks. Patients with Alzheimers dementia cannot perform multiple tasks very well, and that can be explained by the working memory model that the central executive is impaired.
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Figure 2.1 A functional model of the phonological loop. (a) Phonological analysis. (b) Shortterm storage (STS). (c) The programming of speech output. (d) Visual encoding. (e) Grapheme-to-phoneme conversion.(3) The slave systems in the working memory model are the components under the control of the central executive. One of the slaves that deal with sound or auditory information is called the phonological loop or the articulatory loop. It is a short-term storage of auditory memory. Auditory information enters the phonological loop at the phonological store. The articulatory process in this system forms a loop that rehearses the information and prevents the information from decay. Evidences that strengthen this model include the phonological interference of remembering words that sound similar. This is called the effect of phonological similarity, and it suggests that the information in phonological loop is in phonological form. Articulatory suppression happens when the words to remember are not
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spoken aloud. This phenomenon supports the idea about the phonological rehearsal. The phonological loop does not work for only sound information, it also work for other forms of sense that can be transferred to auditory information, for example, names or words can be perceived by the visual system but can be transferred to auditory code and stored in the phonological loop. Another slave system in the working memory model is the visuo-spatial sketchpad. It holds spatial information and other visual senses including shapes, colors, location, and speed of objects. It can be roughly divided into visual, spatial, and kinesthetic components. The information about form and color is stored in the visual cache and be transferred to the central executive via the inner scribe. The inner scribe also works for spatial and movement of objects. The reason why Baddeley put visual information away from the phonological loop is that there is less interference between visual and spatial tasks, and any damage to brain area that impair phonological information still leave the visuo-spatial information intact. The working memory model originally proposed by Baddeley and Hitch only has only three components, the central executive, the phonological loop, and the visuo-spatial sketchpad. In 2000, Baddeley added the other component to the slave system. It is called the episodic buffer. It links information in the phonological loop and the visuo-spatial sketchpad to time, and sets the information in sequence. Have been pointed out in the introduction that memory is the ability of an organism to store, retain, and recall information. The main processes of memory can be these three steps; memory encoding, memory storage, and memory recall.
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Memory encoding is the process that any external information is interpreted into the neurological structure. It starts from the information entering the perceptive organs, transferred to neurological code in the sensory memory, and possibly be encoded again in the long-term storage. The encoding of information can be done in different levels. It may be firstly encoded by chemical gradient in short-term memory, then by cellular modification in long-term memory. After encoding, the information can be stored or retained within the brain. The process of memory storage is important for prolonging the time period before the information is recalled. According to the multi-store memory model, short-term memory storage is readily accessible but prone to lost and is small in the capacity; 7 2 items as proposed by Miller. It can be decayed easily if the information is not rehearsed or was inhibited by the central executive as described in the working memory model. Long-term memory storage, on the other way, can be prolonged after practice and repeated rehearsal. The storage of memory is not well understood, but there are some models that may explain some aspects. The multi-trace distributed model suggested by Semon (1923) and Hooke (1969) suggested that memory is converted to a vector of values and a scalar quantity.(10) The memory attributes then are stored in the pre-existing growing matrix. The matrix can have different traces of information stored together in one place. Another model proposed by John Hopfield, called the neural network model, states that neurons form network with one another with specific activation values.(11) The information is kept in the matrix just like the multi-trace distributed model, but the weight of connection allows the network to store information in different memory patterns. Its difference to multi-trace distributed model is that the matrix does not need to be expanded. The other model of memory storage is the dual-store memory search model or Search of Associative Memory model (SAM).(12) It generates storage in two places similar to the Atkinson-Shiffrin multistore memory model; the short-term store and the long-term store.
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Memory recall is a critical process of memory. There are three main types of recall; free recall, cued recall, and serial recall. According to two-stage theory, the recall process starts with the search of the memory trace and followed by the retrieval process. It is shown in recognition, or the cued recall, that if there is any failure in one of these two processes, recognition can still be successful. Unlike recognition, free recall need complete steps of both the search and the retrieval. The encoding specificity theory added up a suggestion that the memory trace during the search of information in the storage is specific to the situation or the environment the information is encoded. General factors that affect recall can be the amount of attention, motivation, interference, and the context. Tip of the tongue state or Presque vu is one of the failures in the retrieval system of lexical memory when the encoding and storage of memory is still available. The understanding about the categorization of memory and its processes is critical since its abnormalities are sometimes not global but locally specific to only a few types of memory. Disorders in the function of cognitive activities are usually tied with specific structural defects.
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References
1. Kenneth W. Spence JTS. The Psychology of Learning and Motivation: Advances in Research and Theory: Elsevier; 1968 [cited 2012 18 July]. Available from: http://books.google.co.th/books?id=SVxyXuG73wwC&lpg=PA89&ots=CxK3tBOUbx&dq=Atkinso n%2C%20R.%20C.%2C%20%26%20Shiffrin%2C%20R.%20M.%20(1968).%20%20Human%20 memory%3A%20A%20proposed%20system%20and%20its%20control%20processes%22&lr&p g=PA89#v=onepage&q&f=false. McLeod SA. Atkinson and Shiffrin | Multi Store Model of Memory2007 [cited 2012 18 July]: Available from: http://www.simplypsychology.org/multi-store.html. Baddeley A. Working memory: looking back and looking forward. Nat Rev Neurosci. 2003;4(10):829-39. Alan D. Baddeley GH. The Psychology of Learning and Motivation: Advances in Research and Theory: Elsevier; 1974 [cited 2012 18 July]. Available from: http://books.google.co.th/books?id=o5LScJ9ecGUC&lpg=PA47&ots=8y8E3Y7i5&dq=working%20memory%20baddeley%20The%20psychology%20of%20learning%20and%2 0motivation%3A%20Advances%20in%20research%20and%20theory&lr&pg=PA47#v=onepage &q&f=false. Draaisma D. Metaphors of Memory: A History of Ideas About the Mind: Cambridge University Press; 2000 [cited 2012 18 July]. Available from: http://books.google.co.th/books?id=Q0LlL1A9p9cC&lpg=PA93&ots=qr9LnCYZFg&dq=segner% 20coal%20experiment&pg=PA93#v=onepage&q=segner%20coal%20experiment&f=false. Miller GA. The Magical Number Seven, Plus or Minus Two: Some Limits on Our Capacity for Processing Information1956 [cited 2012 18 July]; 63: Available from: http://www.musanim.com/miller1956/. Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11(2):114-26. Tulving E. Episodic memory: from mind to brain. Annu Rev Psychol. 2002;53:1-25. Berntsen D, Jacobsen AS. Involuntary (spontaneous) mental time travel into the past and future. Conscious Cogn. 2008;17(4):1093-104. Kahana MJ. Foundations of Human Memory: Oxford University Press; 2012 [cited 2012 18 July]. Available from: http://books.google.co.th/books?id=NsoKCOzCjCsC&lpg=PA85&ots=y9Vre7VNe5&dq=semon %20hooke%20Multi-
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5.
6.
7. 8. 9. 10.
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11. 12.
Trace%20Distributed%20Memory%20Model&pg=PA85#v=onepage&q=semon%20hooke%20M ulti-Trace%20Distributed%20Memory%20Model&f=false. Hopfield JJ. Neural networks and physical systems with emergent collective computational abilities. Proc Natl Acad Sci U S A. 1982;79(8):2554-8. PMCID: 346238. Raaijmakers JGW. SAM: A theory of probabilistic search of associative memory. The Psychology of Learning and Motivation. 1980;14:207-62.
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Gross Structure of the Brain
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Chapter 3 Gross Structure of the Brain Involved in Memory Processing

Akara Metasuk Many areas of the brain are involved in memory, form cortical to subcortical regions. When talking about memory, most people think about the hippocampus, but this structure may not be involved in all kinds of memory. The prefrontal cortex, likewise, is not required for all processes of memory. For example, it may be involved mainly only in working memory and long-term memory, but not sensory memory. While some cortical structures, such as the medial temporal lobe, are very popular in memory research, it doesnt mean that this area is the basic structure for memory in all aspects. The lobes of the cerebrum, along with the cerebellum, can have vast different implications to memory. Subcortical structures, other than the hippocampus, including the basal ganglia, and amygdala also play such a big role to memory. The frontal lobe, the most anterior part of the brain, separated from the parietal lobe and the temporal lobe by the central sulcus and the lateral sulcus, is involved mainly in the control of voluntary movements. The precentral stripe of the frontal lobe activates voluntary movements, and the cortex is important for making plans, personality and paying attention. The frontal lobe coordinates information for memory especially in working memory.(1) It selects memories for particular events. It is involved in the source monitoring process of memory, which the source of information is put together in the same memory; this is part of retrospective memory which is related dramatically to medial prefrontal cortex. Source monitoring errors occurring after the malfunction of the frontal lobe can be any inability of discriminating thought ideas and spoken ideas, or an imaginary event and a reality. It occurs in patients with amnesia and patients with frontal lobe damage, or even in young
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children. It was suggested that the part essential of the discrimination is the paracingulate gyrus. The frontal lobe is also involved in prospective memory in the way that it selects out, or recall, specific information for planning future actions to fulfill an intention.(2) This is the story of episodic memory, declarative memory, and retrospective memory altogether supervised by the frontal lobe executive functions. The main defect of prospective memory after prefrontal cortex lesion is found basically when the memory is event-based, but not time-based, as shown in the study by Cheng in 2008.(3) The parietal lobe is located behind the frontal lobe, before the occipital lobe, and above the temporal lobe. The central sulcus, the Parieto-occipital sulcus, and the lateral sulcus or Sylvian fissures are the three lines to separate this lobe from the others. The parietal lobe is involved mainly for the voluntary perception of touch by using the postcentral stripe as described by the homunculus. It also multisensorily integrates various forms of sensory information.(4) Other than perception, the parietal lobe is important for spatial coordination of the environment and the self. Damage to this lobe can result as contralateral neglect, Gerstmann syndrome, agraphia, aphasia, apraxia, and acalculia. Related to memory, attention is another topic that this lobe is involved with, but only when the object of attention is more than one.(5) This may be due to the involvement of parietal lobe as the motivator of the loops in the working memory; both in the phonological loop and the visuospatial sketchpad. The temporal lobe is located inferior to the frontal lobe and the parietal lobe under the lateral sulcus. The superior tempral gyrus is generally for the perception of auditory information and the comprehension of language in the Wernickes area. This is why this area is crucial for verbal memory. The ventral temporal cortex is involved in the processing of complex visual stimuli including faces, which is the function of the fusiform gyrus, and
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scenes, which is the function of the parahippocampal gyrus. The medial temporal lobe is the main region of the brain known to be involved for long-term declarative memory formation, especially episodic memory, which works together with the hippocampus.(6) Severe anterograde amnesia is the result of damage to this area. Retrospective memory is not usually defected by the same damage, but mild retrograde amnesia could still happen. The occipital lobe is located at the posterior most of the brain. Its function is known as the center of visual perception. The ventral stream of the pathway from the lateral geniculate nucleus of the thalamus sends visual signals for shape and size of objects, while the dorsal stream sends information about motion and place in space where the object is at. The occipital lobe is involved in visual information; therefore, it is important for the encoding of visual sensory memory. However there is less research that shows the occipital lobe involvement to other processes of memory. The cerebellum is the structure separated away from the lobes of the cerebrum. Its function is to coordinate fine motor controls for timing and accuracy. (Figure 3.1) Its involvement to memory is related to motor learning or procedural memory.(7) Procedural memory can be kept in long-term by the processes of this structure. David Marr and James Albus postulated that climbing fibers of the cerebellum send signals to trigger the synaptic plasticity of parallel fiber of granule cells and Purkinje cells.(8) The signal from the climbing fiber is an error signal. It causes the synapses of the Purkinje cells to be weakened. The studies about motor learning usually is the eyeblink conditioning. The basal ganglia are located inside the brain around the thalamus. It comprises of subthalamic nucleus, substantia nigra, globus pallidus, and striatum; putamen, nucleus accumbens, ventral tegmental area and caudate nucleus. They are involved in the function of eye and motor movement along with motivation towards rewarding behaviors. In memory
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aspect, it is important for some implicit memory specifically motor memory.(9) Damage to basal ganglia can cause an inability to switch tasks during working memory. This can be seen in patients with dystonia, Fahrs syndrome, Huntingtons disease, and Parkinsons disease.
Figure 3.1 Specialization of the cerebellum, the basal ganglia, and the cerebral cortex for different types of learning.(7) Hippocampus is the structure which lies inside the temporal lobe. It is a part of the hippocampal formation; which involves the hippocampus, dentate gyrus, subiculum, and entorhinal cortex. In 1937, James Papez proposed a circuit that showed how hippocampal formation and amygdaloid complex were the substrate of emotional behaviors, and the hippocampus is the key structure for memory consolidation.(10) The circuit starts from the subiculum to mamillary bodies via the fornix, then to anterior thalamic nucleus. From the
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thalamus, it projects via the internal capsule to the cingulated gyrus then to cingulum and down to parahippocampal gyrus, entorhinal cortex, and finally back to the hippocampus. This circuit expressed that emotion is due to the activity of subcortical structures and less about the cortical areas. The hippocampus contains cognitive maps which the cells, called place cells, can fire in different patterns when the organism is placed in different locations.(11) (Figure 3.2) The place cells are believed to be the pyramidal cells in CA1 and CA3 of the hippocampus, or the granule cells in the dentate gyrus. The place cells can be subcategorized into head-direction cells, grid cells, and border cells. The hippocampus is also indicated as the main feature of declarative memory encoding, specifically episodic memory and autobiographical memory, to long-term memory.(12) That is because it is the structure that memory consolidation needs. Damage to this area can directly affect explicit prospective memory, and some retrospective memory which was remembered a few years before the damage. However, semantic memory and procedural memory can still be formed; and recognition tasks, not recalling tasks, can still be corrected without the hippocampus. These functions are usually called in a bigger picture as the result of the medial temporal lobe.
Figure 3.2 Place cell in the hippocampus (a) and grid cell in the medial entorhinal cortex (MEC) (b).(11)
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The amygdala is anterior and inferior to the hippocampus in the medial temporal lobe. It responds to emotional stimuli; therefore, it is certainly involved with emotional memory and fear.(13) It not only enhances emotional memory, but also encodes the memory in the central nucleus of the amygdala and the bed nuclei of the stria terminalis. Classical fear conditioning fails if the amygdala is removed. Damage to the structure can have effects in loss of both appetitive stimuli or motivation and negative stimuli or fear. Memory modulation during long-term memory consolidation is the process that relies on the amygdala. The information can be remembered, or encoded more strongly if the amygdala was enhancing it during learning. The memory modulation can be caused by positive emotion and negative, or stress, emotion. Thats why mild corticosterone administration can enhance long-term memory. The amygdala promotes the interactions between neocortical areas and the temporal lobe for the storage of declarative memory.(14) To understand the functions of the brain, ablation was chosen as the primary procedure in the past. The structure of interest had to be removed and the observation of animal/human behavior followed. Electrical stimulation of specific brain areas takes the same concept to ablation but only in the contradictory way. There are now some imaging techniques that can give clear pictures of the brain structures without dissection. Computed tomography (CT) and magnetic resonance imaging (MRI) are widely used today under the principles of X-ray and atomic magnetization, but these techniques cannot compare how each area is functioning. After the development of electroencephalography (EEG), the functional studies became non-invasive. It records electrical activity of the brain reflected on the scalp. It has high temporal resolution at millisecond time frame but has very low spatial resolution. An improved technique is magnetoencephalography (MEG) which detects magnetic fields produced by neuronal electrical currents. The technique gives high resolution for both spatial and temporal, but still can detect neuronal activities only via the
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scalp surface. To study the functional activities of the inner structures, positron emission tomography (PET) or functional MRI (fMRI) may be applied. PET uses metabolically active molecules such as positron-emitting radionuclide glucose analogue to determine the cellular activity by the amount of glucose uptake. fMRI, on the other hand, measures the difference of the magnetization of the blood since deoxygenated hemoglobin is more paramagnetic than oxygenated hemoglobin. However, though these techniques can indirectly measure the activities of each area in a few millimeters spatial resolution, they still cannot identify the activities of single cells. Multielectrode array (MEA) has been used to solve this problem. Metallic electrodes are inserted into the area of interest. Stereotaxic procedure together with other imaging techniques is applied for the electrodes to be placed in the correct point. In vitro studies have been using MEAs with a few hundred electrodes, and around a hundred electrodes for in vivo studies. The technique is being improved, but it is still impossible to record all single neurons in the brain with this technique. It is concerned that the more the electrodes is the more severe the brain tissue. As stated earlier that there is no structure of the brain that works by itself for every type of memory, different structures can have effects to one another directly or indirectly. However, some areas of the brain may have some functions that are devoted to a few types of memory; therefore, it is worthwhile to know how each memory can be affected by different malfunctions of the brain areas. In the next chapter, I will focus deeper into the cellular structure of the brain that makes up each process of memory.
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References
1. 2. 3. Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6(2):119-30. Martin T. Brain regions and their dynamics in prospective memory retrieval: a MEG study. Int J Psychophysiolo. 2007;64(3):247-58. Cheng HD, Wang K, Xi CH, Niu CS, Fu XM. Prefrontal cortex involvement in the event-based prospective memory: evidence from patients with lesions in the prefrontal cortex. Brain Inj. 2008;22(9):697-704. Halford GS, Cowan N, Andrews G. Separating cognitive capacity from knowledge: a new hypothesis. Trends Cogn Sci. 2007;11(6):236-42. PMCID: 2613182. Berryhill ME, Chein J, Olson IR. At the intersection of attention and memory: the mechanistic role of the posterior parietal lobe in working memory. Neuropsychologia. 2011;49(5):1306-15. PMCID: 3078173. Rugg MD, Yonelinas AP. Human recognition memory: a cognitive neuroscience perspective. Trends Cogn Sci. 2003;7(7):313-9. Doya K. Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr Opin Neurobiol. 2000;10(6):732-9. Marr D. A theory of cerebellar cortex. J Physiol. 1969;202(2):437-70. PMCID: 1351491. Packard MG, Knowlton BJ. Learning and memory functions of the Basal Ganglia. Annu Rev Neurosci. 2002;25:563-93. Bird CM, Burgess N. The hippocampus and memory: insights from spatial processing. Nat Rev Neurosci. 2008;9(3):182-94. Moser EI, Kropff E, Moser MB. Place cells, grid cells, and the brain's spatial representation system. Annu Rev Neurosci. 2008;31:69-89. Di Gennaro G, Grammaldo LG, Quarato PP, Esposito V, Mascia A, Sparano A, et al. Severe amnesia following bilateral medial temporal lobe damage occurring on two distinct occasions. Neurol Sci. 2006;27(2):129-33. Robbins TW, Ersche KD, Everitt BJ. Drug addiction and the memory systems of the brain. Ann N Y Acad Sci. 2008;1141:1-21. Amunts K, Kedo O, Kindler M, Pieperhoff P, Mohlberg H, Shah NJ, et al. Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anat Embryol (Berl). 2005;210(5-6):343-52.
4. 5.
6. 7. 8. 9. 10. 11. 12.
13. 14.
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Cellular and Molecular Structure
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Chapter 4 Cellular and Molecular Structure of the Brain Involved in Memory Processing
Akara Metasuk Discoveries in the behavioral and anatomical neuroscience paved a way for the big change in the understanding of how the mind works, but when it comes to the questions about the modulation of the brain functions, these branches of neuroscience failed to answer. To modulate the functions of the brain; by the use of chemicals or other factors, we need to understand how the structures of the brain communicate, how the cells function, and how the chemicals and mechanisms change. As physiological evidences suggested that the cells in the brain are activated or inactivated specifically to the source of information they learned, it is crucial to understand what the changes of those cells are during being activated or inactivated. Surprisingly, the changes of chemical and cellular components of the brain areas are not static. They are dependent on the types of memory being encountered and the processes of memory the brain is putting itself into. Here I will focus on four processes of memory; encoding, maintenance, recall, and reconsolidation. Memory encoding is the first process that converts perceived information to a biological form that can later be stored and possibly be recalled. The most extensive form of memory being encoded almost all the time people are awake is visual memory. Visual information can be encoded by the process called the visual encoding. In sensory memory, visual memory is encoded in the form of iconic memory. It can be transferred to short-term memory in the form of visuo-spatial sketchpad which was described by Baddeleys model of working memory. The second type of memory being widely encoded is acoustic memory. Acoustic encoding encodes information about sounds and words. It is encoded into the echoic memory a few hundred seconds in sensory memory, and transferred to the
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phonological loop during short-term memory. A word, during being heard, is encoded in the form of echoic memory until the full word is perceived it will be transferred to another form of short-term memory that recognizes the information as a word. Phonological similarity effect (PSE) is the defect of ones ability to encode information; for example words, which have similar sound. PSE happens not only with information being heard, but also with information being read, or lexical information.(1) This means that written words are also encoded in the form of acoustic memory too. Generally, information is encoded separately in the form of visual memory, acoustic memory, tactile memory, gustatory memory, and olfactory memory. After these sensory inputs are gathered, they can be transferred to another form of memory, semantic memory, which requires a process to summarize all of the information into one unit in short-term memory. Sensory information is encoded in different areas depending on the types of information the organism is being exposed to. For example, Iconic memory is encoded in the primary visual cortex, and acoustic memory is encoded in the primary auditory cortex. The encoding may be interpreted as the patterns of neurons being activated, such as the visual map of iconic memory. Short-term memory encoding is due to the existing proteins and chemicals inside and around the cells that are being activated. The short-term changes in the quality and quantity of the chemicals determine how the encoded memory can be retained. The decay of short-term memory can be understood by the degradation or the reuptake of chemicals, for example the neurotransmitters, at the active sites. The changes in the quality of proteins and chemicals depend dramatically on the process of phosphorylation and dephosphorylation.(2) In a prolonged process of chemical modulation, protein synthesis rates may be modified and make permanent changes to the cells.(3) That will be called the long-term memory encoding. The information can be encoded in different
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levels. This is due to the availability of rehearsal. This is called the process of memory maintenance. The maintenance of memory is the process to retain the information for a period of time. Sensory memory is retained for only 200-500 milliseconds while short-term memory and long-term memory can retain the information for up to 1 minute or entire the lifetime, respectively. The difference of the ability to retain information in these memory levels is from the mechanisms they possess. Sensory memory, as from recent knowledge, retains information by the activity of neurons from existing chemicals and protein. When the circuit being activated is recovered back to the normal stage, the information is deleted. Unlike sensory memory, short-term memory maintains information by rehearsal. There is no difference from baseline in protein synthesis. The cells still utilize the existing chemicals and proteins, but the big difference to sensory memory is that the activation of the circuit in short-term memory continually occurs during rehearsal. This can be explained by the phonological loop and the visuo-spatial sketchpad of working memory model. The representation of information in the brain can occur with or without the stimuli. The basic way that the brain stores short-term memory is by chunking. It is the process that a series of information is grouped into single unit. This is the basic idea for the magical number 7 2 which was proposed by George A. Miller in 1956. By this way, it means that neurons that represent different information, but in the same chunk, must fire in synchrony. This is the reason why the prefrontal cortex is required for making attention to different information at the same time. The prefrontal cortex can have more theta band in electroencephalography (EEG) with increasing working memory load.(4) The maintenance of short-term memory can be explained by the prefrontal cortex-basal ganglia working memory model (PBWM).(5-6) It explains that the memory is maintained in the prefrontal cortex, and it receives updating signals from the basal ganglia, specifically the striatum, in Go-NoGo manner.
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Rehearsal of information can be categorized into two topics; maintenance rehearsal and elaborative or relational rehearsal. The information is retained without any association to other subjects in maintenance rehearsal. This is opposite to the elaborative rehearsal that the organism tries to relate the information with other subjects, such as meaning or older life experiences. Elaborative rehearsal is more effective than maintenance rehearsal because of its more extensive depth of information required for the retention of memory. After the information is repeatedly rehearsed, the brain may undergo a more permanent storage of memory in the form of long-term memory. This may be due to the effect gathered from phosphorylation and dephosphorylation of proteins during short-term memory rehearsal. The long-term effect can be the modification of neural synapses which is the result of gene expression and protein synthesis. The two molecular processes that support long-term memory are long-term potentiation and long-term depression. Long-term potentiation (LTP) was demonstrated in 1966 by Terje Lmo in hippocampus of a rabbit.(7) LTP is the activation of a postsynaptic neuron that occurs in a long time.(8-9) The result of this process is synaptic modulation. It improves the communication quality of neurons by increasing the strength of synaptic connections. The strength of synapses induced by LTP is usually considered as the increase of post-synaptic receptors, but to be honest, LTP can pass its effect back to pre-synaptic neuron too. LTP can be considered in three types; Hebbian LTP, Non-Hebbian LTP, and anti-Hebbian LTP. Hebbian LTP follows Hebbs postulate, cells that fire together wire together, by the meaning that depolarization of pre-synaptic neuron causes depolarization and LTP in post-synaptic neuron. Anti-Hebbian LTP is different at the post-synaptic action that it is hyperpolarization that induces LTP. Non-Hebbian LTP is another topic. It does not need any depolarization, from both pre- and post-synaptic neurons for it to occur. LTP is usually NMDA receptordependent. This kind of LTP has four main properties. One is input specificity, or the
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specificity of synapses that can be induced, this means that LTP can hardly spread to synapses faraway. Associativity is another property. It indicates that LTP that occurs in one connection can strengthen and have its effect to the other pathways that share the same synapse. The other one is cooperativity. This property explains how a number of weak stimulations can be collected and induces LTP in one peak point. The last property of LTP is persistence. It indicates that LTP can last for more than a few minutes and possibly to a few months or years. LTP can be talked about in two phases; early LTP, which modifies the protein and chemical components of the cells without gene expression, and late LTP, which is a longlasting effect of new protein synthesis from nucleus. As the main neurotransmitter in learning and memory is glutamate, LTP is usually described in the term of the induction by glutamatergic neurons. Early LTP (E-LTP) induction starts from the activation of a presynaptic neuron that releases glutamate to a post-synaptic neuron. Glutamate binds to AMPA receptors and triggers an influx of sodium ions. Excitatory post-synaptic potential (EPSP) can occur in the post-synaptic neuron if the depolarization state reaches its threshold. If the signal is repeated before the early EPSP decays, the collective amount of sodium ion will increase positive charge in the cell and release magnesium ion from blocking NMDA receptors. After NMDA receptors become active, it will allow calcium ions to enter the cell. These calcium ions can trigger the activity of many proteins including calcium/calmodulin-dependent protein kinase II (CamKII) and protein kinase C (PKC). These proteins will then be the main keys for the maintenance phase of E-LTP. The expression of E-LTP is after CamKII and PKC are activated. These proteins phosphorylate AMPA receptors and increase the receptor activity, then strengthen the synaptic connection.(10-11) They can also increase the rate that AMPA integrates to plasma membrane.
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In late-LTP (L-LTP), the induction starts from the persistent activation of EPSP that not only triggers the activation of PKC and CamKII but also mitogen-activated protein kinase (MAPK) specifically extracellular signal-regulated kinase (ERK) which can be the result of PKC phosphorylation.(12) This event can happen together with the activation of protein kinase A (PKA) which was activated via G protein-coupled receptors. ERK and PKA altogether can translocate to nucleus and phosphorylate cAMP response element-binding protein (CREB), a transcription factor and allow protein synthesis to happen. One of the resulting proteins can increase dendritic spines and receptors for the post-synaptic neuron. L-LTP expression can have effects to pre-synaptic neuron by the process called retrograde signaling. The molecules that are sent back to the pre-synaptic neuron can possibly be nitric oxide and arachidonic acid. However, recent research has focused on cell-adhesion molecules and endocannabinoids anandamide or 2-arachidonoylglycerol (2-AG) which can be synthesized from diacylglycerol (DAG), a product from the activity of metabotropic glutamate receptor-activated phospholipase C (PLC). This idea came from the finding that there is also an increase of synthesis rate of synaptotagmin, a membrane trafficking protein that plays a role in the docking and fusion process of pre-synaptic vesicles. The other resulting protein after L-LTP is protein kinase M (PKM ). It is a protein in an inactive form of PKC. Protein synthesis in L-LTP requires DNA to be the substrate for gene expression.(13) (Figure 4.1 and 4.2) Therefore, the cell needs a specific marker called the synaptic tagging for the proteins to be transported back to the specific synapses that were activated. It was proposed by Frey and Morris in 1997. This is a very important point since it is found that LTP has the input specificity property. Synaptic tags can possibly be molecules or proteins, called plasticity related proteins (PRP), which are activated at local site after LTP. The synaptic tagging hypothesis can help explain about the other properties of LTP too.(14)
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Nevertheless, another theory suggested that the proteins may be translated locally. It was found that mRNA of Arc protein is highly localized at the site of activated synapses, and the Arc proteins are synthesized at the same sites too. This evidence supports the local protein synthesis hypothesis. This model has a problem about how mRNA is shipped to the correct synapses, but later discoveries helped answer the question. Localization elements (LE), zipcodes, and targeting elements (TE) are mRNA sequences that researchers found they may be recognized by RNA-binding proteins. The proteins then form a complex molecule called ribonucleotide protein (RNP) which guides mRNA along the dendritic spine.
Figure 4.1 Critical sites for memory formation in Aplysia neurons. These models outline and compare 11 critical cellular and molecular mechanisms of memory storage that have been identified in both Aplysia sensory neurons and mouse CA1 pyramidal neurons (in Figure 4.2).(15)
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Figure 4.2 Critical sites for memory formation in hippocampal neurons. These models outline and compare 11 critical cellular and molecular mechanisms of memory storage that have been identified in both Aplysia sensory neurons (in Figure 4.1) and mouse CA1 pyramidal neurons.(15) Long-term depression (LTD) is a process that reduces the strength of a connection between neurons that last for a long time. The result is opposite to LTP.(16-17) (Figure 4.3) LTD happens usually because of repeated weak stimulation, but sometimes because of strong synaptic stimulation too. It is considered an important process that counteracts LTP and maintains homeostasis for the brain for not reaching the ceiling level of synaptic strength.(18) An example of LTD which was extensively studied was in CA1 of hippocampus
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where it receives neuronal signals from CA3 Shaffer collaterals. Here, LTP can occur, but the event may turn to LTD when the frequency of calcium influx is lower than usual for a longer time, for instance, LTD happens when the Shaffer collaterals are stimulated at about 1 Hz for 10-15 minutes. The calcium ion influx level is increased for an extended time but in a small level below the threshold that is required to generate LTP. Opposed to LTP which fast and high frequency repeated calcium ion influx trigger the activity of kinases, LTD is characterized as an activation of phosphatases. These proteins dephosphorylate other molecules, thus counteract the actions done by LTP by recruiting AMPA receptors from the plasma membrane. This event is not only occur in Shaffer collaterals of the hippocampus, but also in medium spiny neuron synapses of the striatum, layer III of the visual cortex which receives signals from layer IV, perirhinal cortex, and prefrontal cortex synapses of serotonin. Another different mechanism of LTD is in the connections between climbing fibers and parallel fibers on cerebellar Purkinje neurons. Parallel fibers activate depolarization of Purkinje cells via AMPA receptors and metabotropic glutamate receptors (mGluR). Together with the activation by climbing fibers, they increase calcium ion influx by both directly from voltage-gated channels and intracellular increase by mGluR-activated inositol triphosphate (IP3). PKC is then activated, and it becomes the main cause of AMPA internalization by phosphorylating the receptors. LTD can be retrogradely transferred to pre-synaptic neurons by a retrograde signaling of endocannabinoid receoptor (CB1). This is due to the ability of CB1 to inhibit the activity of adenylate cyclase, reducing the availability of cAMP; therefore, lower the activity of pre-synaptic neuron to be likely to generate LTP in post-synaptic neuron. As described previously, the occurrence of LTP and LTD depend on the frequency and timing of stimulating signal, so called the spike timing-dependent plasticity (STDP). The time frame that can generate synaptic plasticity, whether LTP or LTD is less than 15 milliseconds.(19) If neurotransmitters are released before a back-propagating action
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potential in 15 millisecond time scale, LTP is likely to occur, but if the back-propagating action potential occur 5-15 milliseconds before the neurotransmitter next release, it will become a LTD. STDP of LTD happens by the collective stimulation of both NMDA receptors and CB1 receptors at the same time. LTD plays important roles in increasing signal-to-noise ratio of cortical activity, maintaining neuronal homeostasis, and supporting motor learning characteristics of cerebellum.
Figure 4.3 The relationship between activity, Ca2+ concentration and dendritic spines.(20) Long-term memory is encoded and stored in a more permanent manner by the process called memory consolidation.(21) It can be considered in two stages; synaptic consolidation and system consolidation. Synaptic consolidation is the changes of the
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synaptic structure in the activated pathway due to LTP and LTD. The effect takes a few minutes to occur and can last to about 24 hours. This is due to the process of gene expression and protein synthesis. System consolidation is another subject that occurs in a longer time. It is usually the topic that talks about the involvement of hippocampus that moves memory in any local sites to permanent storage in neocortex. (Figure 4.4) After system consolidation, the memory will become hippocampal-independent. It is sometimes related to the process of implicit or unconscious recall during sleep, but system consolidation can still occur explicitly or consciously during awake.
Figure 4.4 Prefrontal cortex and remote memory.(22) Memory recall is a process that the information is retrieved from the storage in the brain. Two-stage theory of memory recall states that memory recall is processed in two stages; a search of the stored information, and a decision to retrieve the information. Encoding specificity principle support another idea that the information is retrieved from a
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memory trace which can be the other information about events or situations that occurred at the same time with the target information. After the memory is recalled, the information will be reconsolidated.(23-24) Reconsolidation is a process that maintains the strength of information storage in long-term memory. However, the pattern of neuronal connections after reconsolidation can be different from that of consolidation patterns.(25) This happens because the brain deletes some unnecessary connections and adds some new information about the subject. This results in a labile phase of memory that lets scientists to modify or even delete some unwanted or harmful memory such that in patients of post-traumatic stresses disorder. (PTSD) using cognitive behavioral therapy by introducing the patients to the bad memory but adds new good experience to that memory. Reconsolidation is molecularly different to consolidation in the way that it does not require BDNF to occur. On the other hand, Zif268, an immediate early gene is an essential factor that supports reconsolidation, but not consolidation.
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References
1. Acheson DJ, Postle BR, Macdonald MC. The interaction of concreteness and phonological similarity in verbal working memory. J Exp Psychol Learn Mem Cogn. 2010;36(1):17-36. PMCID: 3000525. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001;294(5544):1030-8. Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain. 2012;5(1):14. Wu X, Chen X, Li Z, Han S, Zhang D. Binding of verbal and spatial information in human working memory involves large-scale neural synchronization at theta frequency. Neuroimage. 2007;35(4):1654-62. Atallah HE, Frank MJ, O'Reilly RC. Hippocampus, cortex, and basal ganglia: insights from computational models of complementary learning systems. Neurobiol Learn Mem. 2004;82(3):253-67. Norman KA, O'Reilly RC. Modeling hippocampal and neocortical contributions to recognition memory: a complementary-learning-systems approach. Psychol Rev. 2003;110(4):611-46. Lomo T. The discovery of long-term potentiation. Philos Trans R Soc Lond B Biol Sci. 2003;358(1432):617-20. PMCID: 1693150. Yasuda H, Barth AL, Stellwagen D, Malenka RC. A developmental switch in the signaling cascades for LTP induction. Nat Neurosci. 2003;6(1):15-6. Abraham WC. How long will long-term potentiation last? Philos Trans R Soc Lond B Biol Sci. 2003;358(1432):735-44. PMCID: 1693170. Earnshaw BA, Bressloff PC. Biophysical model of AMPA receptor trafficking and its regulation during long-term potentiation/long-term depression. J Neurosci. 2006;26(47):12362-73. Emptage NJ, Reid CA, Fine A, Bliss TV. Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron. 2003;38(5):797804. Serrano P, Yao Y, Sacktor TC. Persistent phosphorylation by protein kinase Mzeta maintains latephase long-term potentiation. J Neurosci. 2005;25(8):1979-84. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009;61(1):10-26.
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14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
Steward O, Worley PF. A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites. Proc Natl Acad Sci U S A. 2001;98(13):7062-8. PMCID: 34623. Barco A, Bailey CH, Kandel ER. Common molecular mechanisms in explicit and implicit memory. J Neurochem. 2006;97(6):1520-33. Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44(1):5-21. Massey PV, Bashir ZI. Long-term depression: multiple forms and implications for brain function. Trends Neurosci. 2007;30(4):176-84. Perez-Otano I, Ehlers MD. Homeostatic plasticity and NMDA receptor trafficking. Trends Neurosci. 2005;28(5):229-38. Feldman DE. Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex. Neuron. 2000;27(1):45-56. Segal I, Korkotian I, Murphy DD. Dendritic spine formation and pruning: common cellular mechanisms? Trends Neurosci. 2000;23(2):53-7. McGaugh JL. Memory--a century of consolidation. Science. 2000;287(5451):248-51. Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6(2):119-30. Dudai Y. The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol. 2004;55:51-86. Dudai Y. The restless engram: consolidations never end. Annu Rev Neurosci. 2012;35:227-47. Alberini CM, Chen DY. Memory enhancement: consolidation, reconsolidation and insulin-like growth factor 2. Trends Neurosci. 2012;35(5):274-83. PMCID: 3348400.
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Brain Development and Memory Functions
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Chapter 5 Brain Development and Memory Functions during Brain Development

Akara Metasuk Development of a persons ability is the result of two main groups of factors; genetic factors and environmental factors including experiences. Child developmental periods can be considered to be age-related. The stages can be newborn at age 0-4 weeks, infant at 4 weeks 1 year, toddler at 1-3 years, pre-schooler at 4-6 years, school-aged at 6-13 years, and adolescent at 13-20 years. Each stage has optimal development abilities usually considered to be the musts for children. Any deficits in child development can be reflected from the defects in the childs genetics and molecular mechanisms. This is a critical chapter when the society pledges a high expectation on science to clarify how to maximize the most of the brains abilities. The answer may come from the very first steps in the development of the brain possibly early during pregnancy or a few weeks after birth. There were some theories that tried to explain how children are developed. Urie Bronfenbrenner formulated a theory, ecological systems theory,(1) setting the environment to four systems; mesosystem which is the effect of the relations to the child that may influence effects on other microsystems such as home and school, exosystem which have effects to the child indirectly but by the changes of the relations between other family members, macrosystem which is the effect from the culture or the big context in the society, and chronosystem which is a life event that can create a big change to the child. This theory is sometimes called development in context theory or human ecology theory. Jean Piaget proposed another theory to describe how human intelligence is developed. It was called cognitive development theory.(2) He divided a childs age-related stages and attached them with some abilities. At age 0-2 years, it is sensorimotor stage. The child learns sensation and
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movement at this stage. At the age of 2-7 year old, soon comes the preoperational stage. Languages and symbols are the main abilities which can be developed. Imagination is widespread. From 7-15 year old, it is a stage called concrete operational stage. The child can understand abstract thinking. Learning about cause and effect is fast growing. In the late adolescent, the child can develop hypothesis and deductive reasoning. This is called the formal operational stage. Lev Vygotsky, in 1920s, developed cultural-historical activity theory introduced a technique called scaffolding.(3) This technique said that the guiding help of the adults during child learning can add a new ability to the child. Attachment theory by John Bowlby explained that at least one relationship of the child to other person is critical for the development.(4) Erik Eriksons psychosocial development theory suggested eight stages of healthy development composed of hopes (0-2 years), will (2-4 years), purpose (45 years), competence (5-12 years), fidelity (13-19 years), love (20-24 years), care (25-64 years), and wisdom (65 years to death).(5) Sigmund Freuds psychosexual development theory stated that a child possess instinctual libido in five stages;(6) oral at 0-1 year, anal at 1-3 years, phallic at 3-6 years, latency at 6-20 years, and genital at 20 years to death. Although these theories proposed changes in child development in stages, but actually the development is continuous and can be overlapping. The stages proposed are just to predict the ranges of time the abilities should be developed. The child development is chronological with age, but the abilities cannot be developed from just growing older. They require environmental factors. The age-specific changes are due to genetic factors that consider when the abilities are turned on or off. The availability of the genetic control allows specific abilities to be ready to be influenced from the environment. The idea introduces the nature versus nurture debate which concerns about the genetics, or nature, and the personal experiences, or nurture. The internal factors or the nature of the child can likely introduce the child to a certain experience which fits the
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characteristics of the child. This is first characterized by the genetics. On the other hand, the external experiences, or nurture, can also have effects to genetic expressions, so called the experience-dependent plasticity.(7) Some examples of experience-driven internal factor changes are allergic reactions and infections. The development can be considered separately in a lot of aspects including basic physical growth, motor development, language development, or as complex as intellectual development and social-emotional development. The brain is the basic element that prepares a platform for a child to develop new abilities. Memory is an ability of the brain; therefore, the understanding of brain development from embryogenesis to adulthood is essential. The core concept of brain development nowadays is neural development which comprises of generating, shaping and reshaping of the nervous system. The study of brain development can be dated back to the comparison to reptilian brain, mammal brain and human brain. The reptilian brain is comparable to the brain stem. It functions for basic survival including digestion, breathing and heart beating. A more developed brain, the mammal brain, is focused in the limbic system. The areas include amygdala and hippocampus which increase emotion and ability to remember. The last developed brain is the human brain which is focused mainly at the neocortex. It adds the ability to plan and develop stronger social interactions. In biology, brain development starts from the ectoderm layer which forms a neural plate at the dorsal part of the embryo in the third week after the formation of ectoderm.(8) After the fourth week, neural groove is formed and develops to a neural tube. The telencephalon which is the most anterior part of the neural tube will gradually develop to become the brain, and the rest of the posterior parts become the spinal cord. Some cells stop dividing and differentiate to neurons and glial cells. They can migrate to specific areas of the nervous system due to chemical gradients. Lastly, synaptic formation occurs between
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neurons. All of the processes can take about 20 years to complete. The key understanding of the brain development is through the differentiation, migration, outgrowth of axons and dendrites, and guidance of growth cone of neurons. The differentiation, migration, and axonal guidance can be activity-independent while the synapse formation is activity dependent. The first signal is from the mesoderm of the embryo. Mesodermal cells move to the dorsal part of the embryo after gastrulation and form a notochord. The ectodermal cells above the notochord then develop neural plate. The later formation of neural groove creates neural folds which close to become neural tube. This process is called neurulation. After the fourth week after gestation, the process of neural tube should be completed and both ends have to be closed. The differentiation of ectodermal cells to neural cells is controlled by inducer molecules such asfollistatin, noggin, and chordin. These chemicals are produced by the notochord and diffuse upper to the ectodermal layer and inhibit bone morphogenetic protein 4 (BMP4), a transforming growth factor protein (TGF- ), from activating ectodermal cells to epidermis. In the fourth week, the neural tube regionalizes to become prosencephalon, mesencephalon, and rhombencephalon. The procencephalons basal plate, or the inferior area, develops optic vesicle for optic nerve and diencephalon which will become the thalamus and hypothalamus. The alar plate, or the superior area, of prosencephalon expands to develop the telencephalon which will become cerebral hemispheres. The control of neural regionization is under dosoventral control and rostrocaudal control. The dorsoveltral control of neural pattern is mainly by the notochord which is inhibiting effect to BMP4 as described earlier. There is also an inducing agent called Sonic Hedgehog (Shh) which is produced from the notochord. The notochord-produced Shh induces the
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expression of Shh in the floor plate of neural tube. The floor plate-produced Shh then send signals to the other cells in the ectoderm by its gradient. At low concentration, the cells become interneurons, but at higher concentration, they will become motor neurons. The development of sensory neurons at the dorsal area is due to the availability of BMP produced from epidermal ectoderm which is located nearby. The rostrocaudal or the anteroposterior control of neural development is due to retinoic acid and fibroblast growth factor (FGF). Retinoic acid which is widely expressed at the anterior part of the nervous system induces the shaping of the hindbrain and facial nerve by binding to retinoic acid response element (RARE) at 3 region of Hox genes, the developmental genes which have 180 nucleotide-long homeobox. The products of Hox genes can be transcription factors Neuronal migration is a process essential to provide neuronal cell for the whole brain since neural cells are generally divided in subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of the hippocampus. Radial migration from SVZ is important for the supply of neuronal cells in the cerebral cortex. (Figure 5.1) The first group of neurons to migrate is Cajal-Retzius cells which will be formed at the outermost of the cortex. They form bipolar shape and attach to pia surface. Microtubule contraction moves the nucleus to the outer surface by the process called nucleokinesis. Cajal-Retzius cells generate reelin, a protein that guides radial glia for the direction of other neuronal migration. Other neurons are migrated along the radial glia which acts as a migrating fiber for neurons from the ventricle to pia surface. The migration of neurons is considered inside-out. Radial glia itself can differentiate to astrocytes or neurons after finishing neuronal migration. The complete process is called corticogenesis. Apart from radial migration, interneurons can tangential migrate independent of radial glia but dependent on chemical tenascin-R.
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Figure 5.1 Nuclear migration of cell cycle phase of NPCs in the VZ of telencephalon.(9)
After migration, the survival of neurons is up to nerve growth factors (NGF) including BDNF, NT3, and NT4 which the cells sense by their Trk receptors. (Figure 5.2) The secondary effects include the activation of MAPK, Akt, and PKC which increases the availability of CREB for transcriptional process. Another chemical, ciliary neurotrophic factor (CNTF) acts on its receptors to activate JAK kinase. JAK kinase then phosphorylates CNTF receptor, LIFR , and allows the receptors to be free from STAT transcriptional factors. STAT then regulates gene expression in the nucleus. Glial cells can produce neurotrophic factors too. It is glial derived neurotrophic factor (GDNF). Its activation of type 1 receptor phosphorylates Smad proteins which activate gene expression. Synaptic formation in the peripheral nerves, neuromuscular junctions, is mediated by agrin, a molecule that attracts
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acetylcholine receptors clustering. However, in the central nervous system, synaptogenesis is believed to be dependent on neuronal contact to astrocytes. Chemicals released from presynaptic neurons including SynCAM, a cell adhesion molecule, are observed in the cells forming synapses. Neuroligins produced from post-synaptic neuron and -neurexins produced from presynaptic cells can form strong contacts between the two cells. After the formation of synapses, some of synapses may be activity-dependently eliminated. The synapses which are activated strong enough can remain, but the weaker ones may be destroyed. Neurogenesis and synaptogenesis in certain areas such as the hippocampus are the main events that usually reflect the cognitive ability of the brain. They are shown to be lower in aged, stress-induced, or sleep-deprived subjects.
Figure 5.2 Developmental context for activity-dependent neurotransmitter respecification.(10)
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At birth, the brain is not fully developed. Instead, it continues developing to nearly complete at about the age of 20, and it seems the development will never end through the whole life. Because the maturation of the brain continues after birth, and the connections of neurons depend on the activity of the synapses, stimulation to particular pathways of neurons in the right time is important for the brain to maintain its connections. The duration of stimulation is limited and strictly set at only one time in an age, so called the critical period. This should not be confused with another term, sensitive period, which is the duration when the organism has high possibility to develop a skill, though sensitive period and critical period are usually taking the same time. After passing the sensitive periods, children will become more difficult to learn, or may be impossible to learn in the term of critical periods. Most of sensory systems are critical to babies in only 2-3 years after birth. If no stimulus is present to them at that age, it is possible that they will lose that sensory system forever. The brain grows from back to the front. Visual system and auditory system develop after motor skills. The last part of the brain to be developed is the prefrontal area. Sensory systems are most active in their highest peaks before 2 years old. However, they can still be developed in sensitive range until the age of 6. Language acquisition is sensitive at 1.5-3 years old together with fine motor skills which is sensitive until the age of 4. From 4.5-6 years old, the child will be able to do simple mathematics. All of the sensory periods reflect the time when the brain areas involved are best connected. Critical periods, likewise, reflect the time when the systems are refined. Brain structures in memory system may also have some critical periods. For example, the dentate gyrus of the hippocampus may have a critical period to be exposed to memory formation at 2-3 weeks after birth. It was shown by Ida E. J. Aaseb research group that some younger neurons are essential for whole life memory processing.(11) However, it is still unclear whether there exist a critical period for this structure since dentate gyrus
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continues neurogenesis throughout life; therefore, the younger neurons can always be replaced by the new ones. This is an essential field of research that may add new information about how dentate gyrus works for memory storage such that the young neurons hyperplasticity may prepare connection traces for new neurons that will be generated later.
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References
1. Bronfenbrenner U. The Ecology of Human Development: Experiments by Nature and Design: Harvard University Press; 1979 [cited 2012 19 July]. Available from: http://books.google.co.th/books?id=OCmbzWka6xUC&lpg=PA332&ots=ywNXO6VNi9&dq=The %20Ecology%20of%20Human%20Development%3A%20Experiments%20by%20Nature%20and %20Design.%20Cambridge&pg=PA332#v=onepage&q=The%20Ecology%20of%20Human%20 Development:%20Experiments%20by%20Nature%20and%20Design.%20Cambridge&f=false. Jean Piaget BI. Memory and Intelligence: Routledge & Kegan Pal Ltd.; 1968 [cited 2012 19 July]. Available from: http://books.google.co.th/books?id=JYg9AAAAIAAJ&lpg=PR10&ots=gplGtamguS&dq=Memory %20and%20intelligence&lr&pg=PR10#v=onepage&q=Memory%20and%20intelligence&f=false. Lev Semenovich Vygotski MC. Mind in Society: The Development of Higher Psychological Processes: Harvard University Press; 1978 [cited 2012 19 July]. Available from: http://books.google.co.th/books?id=RxjjUefze_oC&lpg=PA1&ots=ogzWW4o5ao&dq=Mind%20in %20Society%3A%20The%20development%20of%20higher%20psychological%20processes&lr &pg=PR13#v=onepage&q=Mind%20in%20Society:%20The%20development%20of%20higher% 20psychological%20processes&f=false. Handbook of Attachment: theory, research, and clinical applications: The guilford Press; 1999. Available from: http://digilib.bc.edu/reserves/py241/aver/py24104.pdf. Erikson EH. Childhood and Society: W.W. Norton & Company, Inc.; 1950 [cited 2012 19 July]. Available from: http://digilib.bc.edu/reserves/py041/lian/py04113.pdf. Felluga DF. On Psychosexual Development2011 [cited 2012 19 July]: Available from: http://www.cla.purdue.edu/english/theory/psychoanalysis/freud.html. Kolb B, Teskey GC. Age, experience, injury, and the changing brain. Dev Psychobiol. 2012;54(3):311-25. Matcheri S. Keshavan RM, Robin M. Murray. Neurodevelopment and Adult Psychopathology: Cambridge University Press; 1997 [cited 2012 19 July]. Available from: http://books.google.co.th/books?id=P5RscUsT4e8C&lpg=PP1&hl=th&pg=PR6#v=onepage&q&f =false. Doi K. Mechanisms of neurotoxicity induced in the developing brain of mice and rats by DNAdamaging chemicals. J Toxicol Sci. 2011;36(6):695-712.
2.
3.
4. 5. 6. 7. 8.
9.
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10. 11.
Spitzer NC. Activity-dependent neurotransmitter respecification. Nat Rev Neurosci. 2012;13(2):94-106. Aasebo IE, Blankvoort S, Tashiro A. Critical maturational period of new neurons in adult dentate gyrus for their involvement in memory formation. Eur J Neurosci. 2011;33(6):1094-100.
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Neurotransmitting Chemicals
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Chapter 6 Neurotransmitting Chemicals Known to be Related to Memory Processing

Akara Metasuk Neurotransmitters are neurochemicals that transfer signals from one neuron to the others by releasing from synaptic vesicles in pre-synaptic neurons and released to have effects on post-synaptic neurons via their receptors. Most of neurotransmitters involved in memory processing are amino acids; glutamate, aspartate, serine, GABA, and glycine. Other forms of neurotransmitter such as monoamines; dopamine, norepinephine, epinephrine, serotonin, and histamine, and other molecular types; acetylcholine, anandamide and nitric oxide, are also involved in memory mediation and modulation. More than 90% of human brain synapses are excited by glutamate and inhibited by GABA. Likewise, the memory system is considered to be affected mostly by these two neurotransmitters. Glutamate or glutamic acid (Glu, E) is an amino acid neurotransmitter that can hardly pass blood-brain barrier, but can enter the brain by using high-affinity transport. It is the major neurotransmitter known to generate synaptic plasticity by causing long-term potentiation (LTP) through NMDA receptors conduction of calcium ions, the basic principle for long-term memory formation.(1-2) On the other hand, excess calcium ion influx, especially when coupled with ischemic or hypoxic, can cause excitotoxicity and cell death instead of neuronal growth by damaging mitochondria and triggering the transcription of pro-apoptotic genes.(3-4) Mitochondria can be damaged directly when calcium is excess in the cytosol and the mitochondrial permeability transition pore is opened. Indirect effect to the cell is the release of reactive oxygen species from mitochondria after their swelling. The result can be mental retardation instead of memory formation. Removal of glutamate from
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synaptic cleft is by sodium ion-dependent glutamate transporters, or excitatory amino-acid transporter (EAAT), which can be found in astrocytes, microglia, oligodendrocytes, epithelial cells, and pre-synaptic neurons. EAAT not only remove glutamate, but also aspartate from extracellular space. It prevents the cells from excitotoxicity and supply glutamate to presynaptic neurons by recycling it. When glial cells uptake glutamate, they convert glutamate to glutamine by glutamine synthetase enzyme. Glutamine can be transported to presynaptic neurons and converted back to glutamate by using glutaminase by mitochondria. Glutamate is packed into synaptic vesicles by another sodium ion-independent glutamate transporter, VGLUT. Excitoxicity can be the result of glutamate transporter failure which may underlie dementia, brain trauma, and age-related neurodegenerative diseases. Once released to synaptic cleft, glutamate can have effects to other cells by binding to ionotropic glutamate receptors; AMPAR, NMDAR, and kainate receptor (KAR), or metabotropic glutamate receptor (mGluR). AMPAR is a sodium/potassium ion channel composed of heterotetrameric subunits of usually two GluR2 subunits and two GluR1, GluR3, or GluR4 subunits. Subunit composition of AMPAR can affect the properties of the channel. The existence of GluR2 in the channel decreases the receptors permeability to calcium ions. The existence of GluR1 subunits allows AMPAR to be phosphorylated by PKC and increase channel conductance during LTP. AMPAR is the main target of inserting into and recruiting from perisynaptic membrane during early LTP and LTD. Similar to AMPAR, NMDAR is a heterotetramer receptor, but comprises of two NR1 and two NR2 subunits, which can be NR2B in postnatal brain and switch to more NR2A in adulthood. NMDAR allow not only sodium and potassium ions but also calcium ion influx, which can act as a second messenger for late LTP. In contrast, KAR is less found in the brain, mainly colocalized with AMPAR and NMDAR in hippocampus, cortex, and retina. It is a sodium/potassium ion channel, and its function is mainly as an autoreceptor on the pre-synaptic regulation of
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vesicle release. mGluR can be considered by three families. mGluR I, mGluR1 and mGluR5, is coupled to Gq increases NMDAR excitability, and mGluR II and III are coupled to Gi/G0 and decrease NMDAR activity. From all of mGluR (mGluR1-8), mGluR7 is considered to be most abundant in the brain. It is an autoreceptor found mainly in the pre-synaptic neurons for the inhibition of neurotransmitter release in the amygdala, hippocampus, and cortex. -aminobutyric acid (GABA) is an amino acid neurotransmitter with basically inhibitory activity to post-synaptic neurons. Its production is related to glutamate since GABA cannot cross blood-brain barrier but can be metabolized from glutamate by glutamate decarboxylase. After taken up by astrocyes at synaptic cleft via GABA transporters, it is metabolized to succinate, alpha-ketoglutarate, and glutamine, respectively. GABAA receptor class is a chloride ion channel, and GABAB receptor class is a metabotropic receptor that stimulates potassium channels, therefore hyperpolarizes neuron. The effect of GABAA receptor activation can be excitatory or inhibitory depending on the direction of chloride ion flow. It was proposed that GABA is excitatory in the brain during brain development before glutamate receptors take that function.(5-6) Drugs that activate GABA receptors can have negative effects to memory in both anterograde and retrograde manners while blockage of
5
GABAA receptors in the hippocampus increases
performance in trace fear conditioning memory task.(7) Acetylcholine (ACh) is synthesized from choline and acetyl-CoA by enzyme choline acetyltransferase and degraded to choline and acetate by acetylcholinesterase. It is widespread in neuromuscular junctions. However, it is a great neuromodulator for neuronal plasticity related to short-term memory and Alzheimers disease.(8-9) (Figure 6.1) Its pathways related to memory can involve the connection from pons to thalamus and cortex, and basal optic nucleus of Meynert and septal nucleus in basal forebrain to neocortex and
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hippocampus.(10) Acetylcholine activity is reduced in Alzheimers disease, but acetylcholinesterase inhibitors can still not treat patients well. Both nicotinic AChR, an ionotropic receptor, and muscarinic AChR, a metabrotopic receptor, can be found in the central nervous system, but the main receptors found are mAChR M1 which are coupled to Gq. They enhance the amplitude of synaptic potentials for LTP development in dentate gyris, CA1, and neocortex. The mechanism that ACh support of LTP on memory may be the NMDA receptor enhancement or the suppression of neuronal adaptation, a process which neuronal response decreases, in the septo-hippocampal cholinergic sytstem. It is possible thet both nicotinic, mainly 7, and muscarinic, mainly M1, ACh receptors may influence hippocampal plasticity which is the basis of memory formation. ACh can also indirectly affect memory by controlling the release of dopamine or GABA in the striatum; nicotinic ACh receptors facilitate and muscarinic ACh receptors attenuate GABA release.
Figure 6.1 Schematic diagram of nicotinic and muscarinic acetylcholine receptor distribution and function in hippocampal neurons.(9)
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Serotonin or 5-hydroxytryptamine
(5-HT) is an important monoamine
neurotransmitter that regulates sleep, appetite, and mood. Its role to appetite is on dopaminergic neurons that are activated during food consumption. Serotonin receptors on these cells shut off dopamine release and therefore reduce appetite, aggressive behavior, anxiety, and depressive behavior. It cannot cross blood-brain barrier, but can be synthesized from tryptophan amino acid, which is soluble in the barrier, by tryptophan hydroxylase enzyme (TPH) and amino acid decarboxylase (DDC). It can be reuptaken to pre-synaptic neurons by serotonin transporters (SERT) or be degraded by monoamine oxidase enzyme (MAO) and aldehyde dehydrogenase to 5-HIAA. There are 7 families of serotonin receptors. All of them are metabotropic except 5-HT3 which is ionotropic to sodium and potassium ions. 5-HT1 and 5-HT5 receptors are coupled to Gi/G0 thus are inhibitory. In contrast, 5-HT4, 5-HT6, and 5-HT7 are Gs coupled and are excitatory by increasing cAMP. 5HT2 is also excitatory but it is coupled to Gq therefore excites post-synaptic neurons by increasing DAG and IP3. 5-HT1A is found on the pre-synaptic neurons therefore can act as an autoreceptor. 5-HT1A, 5-HT3, and 5-HT1B antagonists are shown to improve memory while the antagonism of 5-HT2A/2C and 5-HT4 has an opposite effect. The most exclusively expressed 5-HT receptors are 5-HT6 which its antagonists augment memory functions in spatial learning and object discrimination tasks.(11-12) Drugs of abuse, like methamphetamine, decreases SERT expression, and therefore affect memory performance. Norepinephrine (NE) or noradrenaline is a catecholamine or monoamine neurotransmitter synthesized from dopamine by dopamine -hydroxylase enzyme. Its structure is similar to dopamine since the amino acid substrate for these two neurotransmitters is tyrosine. NE can be reuptaken to pre-synaptic neurons or glial cells by
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norepinephrine transporter (NET). Another transporter usually mentioned to the availability of NE is vesicular monoamine transporter (VMAT) which is critical for packaging of NE to synaptic vesicles. Degradation of NE is processed by catechol-O-methyl transferase (COMT) or monoamine oxidase (MAO). NE function is devoted to sympathetic response. It increases heart rate and blood pressure by releasing from locus coeruleus neurons of the pons. The projection of neurons in this area destines in spinal cord, amygdala, hippocampus, thalamus, striatum, and cortex. NE function is through adrenergic receptors. There are two subtypes of adrenergic receptors;
1
and
2
. All of them are metabotropic. receptor is inhibitory by being
receptor is excitatory by being coupled to Gq while
coupled to Gi. All types of
receptors are excitatory by linking to Gs. Emotional arousal receptor system in this area is
activates brain stem locus coeruleus. Adrenergic
activated and may enhance attention, decision making, and neuronal plasticity in the amygdala and the hippocampus for emotional-related memory consolidation/reconsolidation and increase cellular excitability.(13-15) Dopamine (DA) is another catecholamine neurotransmitter. It is synthesized from tyrosine by tyrosine hydroxylase (TH) mainly in substantia nigra, thalamus, and ventral tegmental area. It does not diffuse in blood-brain barrier; therefore, L-DOPA, a precursor, is given instead of DA. Its reuptake mechanism is via dopamine transporter (DAT) or NET. It can be degraded by COMT or MAO just like NE. There are four major pathways of DA in central nervous system. Mesolimbic pathway connects ventral tegmentum to nucleus accumbens. It is also called the reward pathway. Mesocortical pathway sends signal from ventral tegmentum to frontal cortex involved in motivation and cognitive functions including memory and attention. Nigrostriatal pathway transmits signal from substantia nigra to striatum. It acts as a part of basal ganglia motor loop. Tuberoinfundibular pathway is the DA
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connection from hypothalamus to anterior pituitary for the release of prolactin. Dopamine receptors are metabotropic and comprise of two families; D1-like and D2-like. D1-like family receptors are coupled to Gs. They are D1 and D5 receptors. D2-like family receptors are D2, D3, and D4. They are coupled to Gi. The main receptors responsible for cognitive process are D1 and D4 receptors. DA is involved in cognitive processes from working memory to attention by the interaction between the striatum and the prefrontal cortex.(16-18) It also enhances LTP in the hippocampus in a period timescale when DA is released before an event of memory encoding thus biases what to be remembered. Glycine (Gly) is the smallest amino acid that can be synthesized from serine by serine hydroxymethyltransferase (SHMT). It can be degraded by glycine decarboxylase complex (GCS), serine dehydratase (SDH), or D-amino acid oxidase (DAAO). Glycine acts as an inhibitory neurotransmitter in spinal cord and brainstem because of glycine receptor GlyR ionotropic activity to chloride ion. However, it can be excitatory due to its function as a co-agonist to glutamate at NMDA receptors in the hippocampus.(19-20) Glycine may also modulate memory by means of sleep.(21) Neuropeptides are peptides that can act as neurotransmitters, but they differ from general neurotransmitters by their stability. They are packaged into dense-core vesicles, not small synaptic vesicles, and can be located anywhere in the cell, not only at axon terminals. They are co-expressed with conventional neurotransmitters; for example, neuropeptide Y is found in neurons producing NE or GABA, and substance P is colocalized in neurons that produce ACh and 5-HT. Substance P (SP) is expressed in glutamate-producing sensory neurons and is involved in nociception, and in vomiting center in medulla together with the production of ACh, DA, and 5-HT. An important SP receptor is neurokinin 1 (NK-1) which is a G protein-coupled receptor. NK-1, in central nervous sytem, is distributed in 5-HT and
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ACh neurons in hypothalamus and amygdala to modulate emotion. It has a memorypromoting effect.(22-24) Injection of SP in the ventral pallidum shows an increase of ACh in the frontal cortex and DA in nucleus accumbens. Neuropeptide Y (NPY), another neuropeptide is released from hypothalamus to regulate appetite and block nociception. Y1 and Y5 receptors have stimulating effect while Y2 and Y4 receptors have inhibitory effect for NPY.(25-27) Neuropeptide S (NPS) is also found in amygdala, and its binding to NPS receptors suppresses appetite and anxiety, induces wakefulness and hyper-sexuality, and adds up the activity of dopamine in mesolimbic or reward pathway. Its effect in amygdala is important for fear memory by increasing the release of Glu.(28-29) Other peptide neurotransmitters are opioid peptides; enkephalin, dynorphin, and endorphin. Enkephalin binds to opioid receptors to regulate nociception.(30) Dynorphin has an opposite effect opioid receptors, but it also has nociceptive effect via as an analgesic substance via
bradykinin receptors.(31) Endorphin is produced from pituitary gland and hypothalamus. It is highly secreted in response to excitement, exercise, love, orgasm, and pain. Its synthesis is from pro-opiomelanocortin (POMC). It has high affinity to presynaptic therefore enhances dopamine pathways activation. Endorphin has low affinity to and
1 1
opioid , ,
receptors, the same receptor in response to morphine. Its effect is inhibitory to GABA;
2
opioid receptors, but the activation of
opioid receptors may contribute to the
deficits in learning and memory.(32) Nitric oxide (NO) is a gaseous molecule that sometimes referred to as a neurotransmitter, but it is not released from synaptic vesicles; instead it can diffuse from one cell to the others. The effect of NO is not limited to neurons connected by synaptic cleft, but it can have effects to any neurons nearby. Its effect is short-lived though theres no enzymatic breakdown or reuptake. Its major role is relaxation of muscle. NO can stimulate
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guanylate cyclase to produce cGMP which can activate protein kinase G (PKG) to phosphorylate other proteins.(33-34) Endocannabinoids are large molecular weight chemicals that activate cannabinoid receptors; CB1 and CB2. CB1 is expressed in hippocampal formation, basal ganglia, cerebellum, and neocortex.(35-37) It is activated by anandamide (Narachidonoylethanolamide, AEA) and 2-arachidonoyl glyceride (2-AG) in pre-synaptic neurons to inhibit the release of Glu and regulate anxiety-dependent behaviors including increased exploration, increased social interactions, and suppression of aggressive behavior. However, the effect of CB1 activation on GABA neurons is in opposite way. This is called retrograde signal because AEA and 2-AG are released from post-synaptic neurons. Histamine is a chemical known to be released for inflammation of immune response. It is also released from tuberomammillary nucleus of posterior hypothalamus that project to cortex. Its neurotransmitter function is the induction of wakefulness. There are four types of histamine receptor, but H1 and H3 are the ones that are expressed in the brain. H1 is Gqcoupled and is activated during awake. Its activation inhibits potassium channel thus increases neuronal excitability. H3 is a Gi-coupled autoreceptor that inhibits the release of DA, GABA, ACh, NE, and 5-HT to control satiety.(38-40) Apart from the regulations of neurotransmitters from neurons, glial cells are playing some roles to control the abundance of these chemicals such as that found in the recycling of glutamate. Most of glial cells coping with the level of chemicals around neurons are astrocytes. (Figure 6.2) They are also controlling the physiology of the brain with their water channels, aquaporin (AQP4). AQP4 is related to astrocytic Ca2+ signaling and memory consolidation.(41-42) Its function is also related to neural stem cell proliferation, cell fate specification, differentiation and migration.(43)
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Figure 6.2 The astrocytic process is the third active element forming the tripartite synapse.(44) Neurotransmitters are the main chemicals that allow the brain areas to communicate and perform functions relating to one another. The effects of neurotransmitters are usually short, as measured in seconds. Its long-term effects require repetitions. In contrast, some chemicals released from the brain which have functions for other organs in the body and be transported back to have more persistent effects to the brain. These chemicals are neurohormones. Some of important hormones and their downstream molecules will be the main story in the next chapter.
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References
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Tully K, Bolshakov VY. Emotional enhancement of memory: how norepinephrine enables synaptic plasticity. Mol Brain. 2010;3:15. PMCID: 2877027. Puig MV, Miller EK. The role of prefrontal dopamine d1 receptors in the neural mechanisms of associative learning. Neuron. 2012;74(5):874-86. Roesler R, Schroder N. Cognitive enhancers: focus on modulatory signaling influencing memory consolidation. Pharmacol Biochem Behav. 2011;99(2):155-63. Lisman J, Grace AA, Duzel E. A neoHebbian framework for episodic memory; role of dopaminedependent late LTP. Trends Neurosci. 2011;34(10):536-47. PMCID: 3183413. Mohler H, Rudolph U, Boison D, Singer P, Feldon J, Yee BK. Regulation of cognition and symptoms of psychosis: focus on GABA(A) receptors and glycine transporter 1. Pharmacol Biochem Behav. 2008;90(1):58-64. Xu TL, Gong N. Glycine and glycine receptor signaling in hippocampal neurons: diversity, function and regulation. Prog Neurobiol. 2010;91(4):349-61. Bannai M, Kawai N. New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. J Pharmacol Sci. 2012;118(2):145-8. Hasenohrl RU, Souza-Silva MA, Nikolaus S, Tomaz C, Brandao ML, Schwarting RK, et al. Substance P and its role in neural mechanisms governing learning, anxiety and functional recovery. Neuropeptides. 2000;34(5):272-80. Zlomuzica A, Dere E, Huston JP, de Souza Silva MA. NK(3) receptor agonism promotes episodic-like memory in mice. Neurobiol Learn Mem. 2008;90(2):420-5. Herpfer I, Katzev M, Feige B, Fiebich BL, Voderholzer U, Lieb K. Effects of substance P on memory and mood in healthy male subjects. Hum Psychopharmacol. 2007;22(8):567-73. Morley JE, Flood JF. Neuropeptide Y and memory processing. Ann N Y Acad Sci. 1990;611:226Rangani RJ, Upadhya MA, Nakhate KT, Kokare DM, Subhedar NK. Nicotine evoked improvement in learning and memory is mediated through NPY Y1 receptors in rat model of Alzheimer's disease. Peptides. 2012;33(2):317-28. Redrobe JP, Dumont Y, St-Pierre JA, Quirion R. Multiple receptors for neuropeptide Y in the hippocampus: putative roles in seizures and cognition. Brain Res. 1999;848(1-2):153-66. Jungling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, et al. Neuropeptide Smediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron. 2008;59(2):298-310. PMCID: 2610688.
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Chapter 7 Hormonal Regulations of Memory

Akara Metasuk The brain is not a stand-alone structure. It communicates with other organs throughout the body by its neural connections. Not only in neural aspects, can chemicals released from the brain to the blood stream also have steady effects to target organs. These chemicals are called neurohormones; for instance those released from the pituitary are gonadotropin-releasing hormone, growth hormone, prolactin, adrenocorticotropin-releasing hormone, thyrotropin-releasing hormone, antidiuretic hormone, and oxytocin. These hormones and their secondary/tertiary messengers in their pathways usually have feedback effects to the brain. It means that the regulation of the body is mainly by the brain, and there are some chemicals, and even hormones from other organs, released back from the body that can shape the brain, and certainly have effects on its memory performance. It is critical to understand how these chemicals have effects to the functions of the brain since their effects are usually prolonged, but the actions may be manipulated by environmental stimuli. Gonadotropin-releasing hormone (GnRH) is a peptide hormone synthesized in the preoptic area of the hypothalamus and secreted in the hypophysial portal bloodstream to the pituitary gland.(1) The activation of its receptors (GnRHR) on gonadotrophs at the anterior pituitary has effects on phospholipase C (PLC) which triggers gonadotropins secretion; follicle-stimulating hormone (FSH) is release at low-frequency GnRH pulses, and luteinizing hormone (LG) is released at high-frequency GnRH pulses. FSH stimulates the growth of ovarian follicles in females. When the follicle grows to its 8-10 mm diameter, estradiol is released, and it adds up the pulse frequency of GnRH release, but suppresses the amount of GnRH, from hypothalamus, thus decreases FSH production while induces LH
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secretion. In males, FSH stimulates meiosis of spermatocytes and enhances the production of androgen-binding protein in Sertoli cells of testes. After the release of estrogens from female follicle, LH triggers ovulation and converts the follicle to corpus luteum which produces progesterone. LH also supports the production of androgens and estradiol from the ovary. In males, LH stimulates the production of testosterone, an androgen, from Leydig cells of testes. Androgens are steroid hormones that control the development of male organ and secondary characteristics.(2-3) One of its forms that can be metabolized to testosterone and estrone, a subtype of estrogens, is androstenedione. Androgens play important roles in the control of brain structures that reflect the sex differences. Their level also has subtle effects to aggression. Testosterone is produced in males 8 times more than female, but female is more sensitive to it. It is increased, in both men and women, when people are sexually attracted to the other person. The level is changed from normal during 1-2 years of relationship and falls down to normal level after that. Low level of testosterone is related to cognitive decline which can possibly be a risk factor of Alzheimers disease, but on the other hand, its hyper-secretion induces aggression. However, hormone replacement therapy in hypogonadal males did not show aggressive behavior; therefore, aggression may not be directly associated with too much testosterone but the imbalance of testosterone level. In females, secondary characteristics are triggered by estrogens. There are four types of estrogens; estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4). The least abundant one is estrone. In the same way, estetrol is less synthesized since it is only produced during pregnancy. Estriol is the most abundant one, but its potency is 80 times less substantial than estradiol; therefore, estradiol (E2) becomes the most effective one for
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female hormone treatments. Its low level is related to depression in postmenopausal women and obsessive-compulsive disorder (OCD) which in turn can be restored by the treatment with estrogens or aromatase, an enzyme that converts testosterone to estrogens. Estradiol binds to estrogen receptors; ER and ER , then enter nucleus to regulate transcription. Its role in the brain also includes neuroprotection by its antioxidant activity. Another female hormone is progesterone which is derived from pregnenolone, a precursor for aldosterone. Its actions to apoptotic genes and to the inhibition of GSK-3 pathway are enhanced in the presence of estrogens. Its neuroprotective effect to the brain is the reduction of inflammation during and after traumatic brain injury.(4-6) Growth hormone (GH) comprises of 191 amino acids in its peptide chain. It is produced from somatotrophs in the anterior pituitary after the release of GH-releasing hormone and GH-inhibiting hormone from the hypothalamus. Its function is related to anabolic reactions for the stimulation of cartilage cell division via MAPK/ERK pathway. JAK/STAT pathway in the liver is also activated by GH for the release of insulin-like growth factor 1 (IGF-1) which promotes bone growth. GH can have other effects including calcium retention, increasing muscle mass, and boosting immune system. Its roles in the brain involve increasing appetite, improving memory, mental alertness, motivation, and working capacity.(7-8) However, GH is hardly transported across the blood-brain barrier. Therefore, its effects may come from its metabolites in the circulating blood, for example IGF-1. Prolactin (PRL) is a peptide hormone known to be related to lactation in mammary glands. Lactotrophs are controlled by the inhibitory dopaminergic neurons from arcuate nucleus and stimulatory effect by thyrotropin-releasing hormone (TRH). Its synthesis can be upregulated by progesterone, but PRL itself decreases the level of estrogen and testosterone. PRL role in the central nervous system is by stimulating the proliferation of
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oligodendrocyte precursor cells. It is also released in response of chronic stress. This is due to the expression of PRL in the paraventricular nucleus (PVN) of the hypothalamus. Infusion of PRL which may have effects to PRL receptors, which are mainly in the choroid plexus, is shown to decrease coticotropin secretion therefore decreasing the responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis.(9) Adrenocorticotropic hormone (ACTH) or corticotrophin is a peptide hormone produced from the anterior pituitary and its effect is on the adrenal cortex by increasing the synthesis of corticosteroids; glucocorticoids and mineralocorticoids. Its function is directly related to the HPA axis in response to stress. It is metabolized from pre-proopiomelanocortin (pre-POMC) which is also the precursor of lipotropin, melanotropin (MSH), endorphin, enkephalin, and POMC. Its regulation is controlled by corticotrophin-releasing hormone (CRH) from the hypothalamus. Short-term inhibition of ACTH release starts from the adrenal cortex glucocorticoids which block CRH secretion from hypothalamus. In long-term, glucocorticoids can inhibit the expression of POMC. Glucocorticoids, usually referred to as its subtype cortisol, have main effects to the retention of blood glucose, but they also are involved as the enhancer of flashbulb memories especially in emotionally arousing events.(10-13) They have dose-dependent effect since high dose of glucocorticoids can inhibit the retrieval of memory. The action initiates at the cytosolic glucocorticoid receptors (GR) which, after binding to glucocorticoids, translocate to nucleus and regulate gene expression by binding to glucocorticoid response elements (GRE) in the promoter of the target genes. (Figure 7.1 and 7.2) One of its targets is lipocortin-1, an anti-inflammatory protein. Acute stress can impair memory, but it may enhance memory if the context of stress is matched to the information to be encoded. If the stress is not induced before encoding, the information will tend to be forgotten. In contrast to acute stress, chronic stress induces sympathetic response and the body loses its homeostasis; therefore impairs memory.
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Because of the activated state of the brain during acute stress, the reaction time is reduced and increases working memory. However, anxiety during stress may have an opposite effect to working memory. Long-term memory consolidation is improved with stress, but the reconsolidation of other information is affected.
Figure 7.1 Differential effects of stress hormones on AMPA receptor trafficking.(14) Thyrotropin-releasing hormone (TRH) is a peptide hormone synthesized from the paraventricular nucleus of the hypothalamus. It stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary. The effect of TSH is the release of thyroid hormone, including thyroxine, from thyroid gland which increases metabolic rate, neurogenesis, neuronal differentiation, neuronal migration, myelination, and acts synergically with GH to regulate bone growth. It has big roles to the brain, but most of the studies reported its importance to only during brain development. Some studies showed that thyroid hormone is related to mood disorders, which is consistent with the vast amount of thyroid receptor in the limbic system. The effects of thyroid hormone to mood may be
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through the elevated brain metabolism, or indirectly via neurotransmitters primarily serotonin and norepinephrine by increasing neurotransmission, decreasing autoreceptor 5-HT1A sensitivity and increasing 5-HT2A sensitivity.(15-16)
Figure 7.2 Schematic representation of the signaling and epigenetic pathways in granule neurons of the dentate gyrus thought to be involved in the consolidation process of memory formation after a psychologically stressful challenge.(10) Antidiuretic hormone (ADH) or vasopressin is a peptide hormone synthesized in the hypothalamus, stored and released from posterior pituitary. It controls the balance of blood plasma osmolarity by regulating the reabsorbtion of molecules at the kidneys since its activation of V2 receptors promotes the insertion of aquaporin-2 to cell membrane. ADH also
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has functions in the brain. Its effect to memory is the enhancement of memory formation but the mechanism is still controversial.(17-18) Desmopressin, a synthetic ADH is given to reduce urine production likely has some nootropic or memory-enhancing effect, but no proof has been found. Vasopressin receptors are distributed in the reward pathway specifically in the ventral pallidum. Pair-bonding, satisfaction, affection, cohesion, aggression, and social behavior were suggested to be affected by having low ADH level and its gene variation especially in males. ADH is very close to oxytocin in various aspects including the chemical structure, the chromosome where the gene is located, and the synthetic site. Oxytocin (Oxt) is a peptide hormone produced in magnocellular neurons and released from the posterior pituitary. It is released in females during labor by the stimulation of uterus and cervix, and at the nipples during breastfeeding. It triggers uterine contraction before birth, and promotes wound healing since it reduces inflammation by decreasing the level of cytokines. During child delivery, oxytocin from mother crosses the placenta to fetal brain and switches the action of GABA from excitatory to inhibitory. This is important for the prevention of hypoxia during delivery. It is also related to orgasm, pair-bonding, maternal behaviors, erections, and reducing anxiety. Oxytocin is a good treatment for autism. It increases affective speech and decreases repetitive behaviors in the patients. The ability to interpret emotions is also improved. Some studies have drawn a relationship between the affects in the oxytocin receptor (OXTR) and autism. Its positive effects to memory are narrowed to human faces, fear, and social information, but have negative effects to other memories.(19-21) Melatonin is a hormone produced from pineal gland. Blue light (460-480nm) activates photosensitive ganglion cells in the retina then to suprachiasmatic nucleus (SCN) of the hypothalamus. SCN is the central control system for circadian rhythm. The signal sent
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to pineal gland suppresses melatonin which normally induces drowsiness. Melatonin also has antioxidant activity. It scavenges hydroxyl radical, nitric oxide, and oxygen radicals. This action prevents any damage to DNA and mitochondria. It also enhances immunity by acting on melatonin receptors (MT1 and MT2) and support cytokine production. As melatonin induces sleep, high dose of melatonin can increase REM sleep time therefore enhance dreaming which then have beneficial effects to long-term memory formation. It was shown than melatonin has protective effects by preventing neuronal death and amyloid beta protein aggregation after amyloid beta protein exposure in Alzheimers disease. It also prevents the hyperphosphorylation of tau protein. Depression related to circadian disturbance can also be treated with melatonin. Melatonin effects to long-term potentiation are found to be negative in the dentate gyrus by modulation of NMDA receptor function. (Figure 7.3) It reduces neuronal excitability. This suggests the circadian rhythm effects to learning.(22-23)
Figure 7.3 Working model, illustrating the hypothesized rhythmic modulatory role of endogenous melatonin on memory processing.(24)
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Insulin is a peptide hormone produced by pancreas to control the level of sugar and fat. It induces the liver and muscle cells to uptake glucose and metabolize to glycogen. It maintains the level of fat by inhibiting the release of glucagon, which counteracts insulin and regulates lipolysis. Insulin can be synthesized in the central nervous system by pyramidal neurons in the cortex, olfactory bulb, hippocampus, hypothalamus, and amygdala to regulate metabolism for neuronal growth and differentiation. The role of insulin to glucose transport in the brain may not be direct but via the insulin receptors (IR) or the regulation of the expression of glucose transporter (GLUT). Decreased level of insulin also has effects to impaired memory.(25-26) This may be the results that it modulates the expression of NMDA receptors therefore supports long-term potentiation. In this and the previous chapters, neurotransmitters and hormones have shown to give acute and chronic effects to the brain. Some are positive, and the others are negative as most of the effects promote neuronal plasticity or neuronal death. These events will be the main topics for the following chapter.
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References
1. Wang L, Chadwick W, Park SS, Zhou Y, Silver N, Martin B, et al. Gonadotropin-releasing hormone receptor system: modulatory role in aging and neurodegeneration. CNS Neurol Disord Drug Targets. 2010;9(5):651-60. PMCID: 2967575. Rizk A, Robertson J, Raber J. Behavioral performance of tfm mice supports the beneficial role of androgen receptors in spatial learning and memory. Brain Res. 2005;1034(1-2):132-8. Zuloaga DG, Puts DA, Jordan CL, Breedlove SM. The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation. Horm Behav. 2008;53(5):613-26. PMCID: 2706155. Ooishi Y, Kawato S, Hojo Y, Hatanaka Y, Higo S, Murakami G, et al. Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J Steroid Biochem Mol Biol. 2012;131(1-2):37-51. Mukai H, Kimoto T, Hojo Y, Kawato S, Murakami G, Higo S, et al. Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochim Biophys Acta. 2010;1800(10):1030-44. Daniel JM. Effects of oestrogen on cognition: what have we learned from basic research? J Neuroendocrinol. 2006;18(10):787-95. Aberg ND, Brywe KG, Isgaard J. Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. ScientificWorldJournal. 2006;6:53-80. Wass JA, Reddy R. Growth hormone and memory. J Endocrinol. 2010;207(2):125-6. Fraga MC, Moura EG, Silva JO, Bonomo IT, Filgueiras CC, Abreu-Villaca Y, et al. Maternal prolactin inhibition at the end of lactation affects learning/memory and anxiety-like behaviors but not novelty-seeking in adult rat progeny. Pharmacol Biochem Behav. 2011;100(1):165-73. Trollope AF, Gutierrez-Mecinas M, Mifsud KR, Collins A, Saunderson EA, Reul JM. Stress, epigenetic control of gene expression and memory formation. Exp Neurol. 2012;233(1):3-11. Schoenfeld TJ, Gould E. Stress, stress hormones, and adult neurogenesis. Exp Neurol. 2012;233(1):12-21. Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25(2):181-213. Korosi A, Naninck EF, Oomen CA, Schouten M, Krugers H, Fitzsimons C, et al. Early-life stress mediated modulation of adult neurogenesis and behavior. Behav Brain Res. 2012;227(2):400-9.
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Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat Rev Neurosci. 2010;11(10):675-81. Smith JW, Evans AT, Costall B, Smythe JW. Thyroid hormones, brain function and cognition: a brief review. Neurosci Biobehav Rev. 2002;26(1):45-60. Rivas M, Naranjo JR. Thyroid hormones, learning and memory. Genes Brain Behav. 2007;6 Suppl 1:40-4. Pan YF, Chen XR, Wu MN, Ma CG, Qi JS. Arginine vasopressin prevents against Abeta(25-35)induced impairment of spatial learning and memory in rats. Horm Behav. 2010;57(4-5):448-54. Alescio-Lautier B, Paban V, Soumireu-Mourat B. Neuromodulation of memory in the hippocampus by vasopressin. Eur J Pharmacol. 2000;405(1-3):63-72. de Oliveira LF, Camboim C, Diehl F, Consiglio AR, Quillfeldt JA. Glucocorticoid-mediated effects of systemic oxytocin upon memory retrieval. Neurobiol Learn Mem. 2007;87(1):67-71. Savaskan E, Ehrhardt R, Schulz A, Walter M, Schachinger H. Post-learning intranasal oxytocin modulates human memory for facial identity. Psychoneuroendocrinology. 2008;33(3):368-74. Heinrichs M, Meinlschmidt G, Wippich W, Ehlert U, Hellhammer DH. Selective amnesic effects of oxytocin on human memory. Physiol Behav. 2004;83(1):31-8. Gerstner JR, Lyons LC, Wright KP, Jr., Loh DH, Rawashdeh O, Eckel-Mahan KL, et al. Cycling behavior and memory formation. J Neurosci. 2009;29(41):12824-30. Permpoonputtana K, Mukda S, Govitrapong P. Effect of melatonin on d-amphetamine-induced neuroglial alterations in postnatal rat hippocampus and prefrontal cortex. Neurosci Lett. 2012. Rawashdeh O, Maronde E. The hormonal Zeitgeber melatonin: role as a circadian modulator in memory processing. Front Mol Neurosci. 2012;5:27. PMCID: 3295223. Huang CC, Lee CC, Hsu KS. The role of insulin receptor signaling in synaptic plasticity and cognitive function. Chang Gung Med J. 2010;33(2):115-25. de la Monte SM. Insulin resistance and Alzheimer's disease. BMB Rep. 2009;42(8):475-81.
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Effects of Cellular Changes to Memory
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Chapter 8 Effects of Cellular Changes to Memory; Neuronal Plasticity and Apoptosis

Akara Metasuk Cellular structural changes of neuronal cells are the downstream response to neuronal stimuli. In learning and memory, the structural changes of neurons are in the control of several gene expressions in molecular level whose details are in chapter 4. Learning is usually considered to strengthen neuronal connections by synaptogenesis, axonal outgrowth, and neurogenesis. The terms are always linked to neuronal plasticity or neuroplasticity. Nevertheless, neuronal activities that promote learning and memory do not always be productive. Some of them may undergo some changes in negative ways; neurodegeneration, to be said. Programmed-cell death and apoptosis are the hot topics in neuroscience for a long time. They are the basics for every disease in the nervous system. Mitochondrial malfunction is another subfield that is usually studied together with the defects of cell survival. In this chapter, neuronal plasticity and apoptosis will be focused in both positive and negative ways to memory. Neuroplasticity is the changes in the structure of the nervous system. The changes here can be the gross structural changes during development, or the cellular changes which occurs throughout life or in the remapping process after injury. Though some studies in the 18th century had disclosed the fact that the nervous system can rewire, the evidence of neuroplasticity became clearer in the early 20th century after the experiments by Paul Bach-y-Rita who demonstrated that blind people can perceive tactile stimuli and interpret them as visual information.(1) It was explained that one sense can take over the other damaged sense. This requires the brain to rewire. The discoveries about neuroplasticity shed their light to various applications to regeneration after injury and neural prosthesis. The
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treatments to some diseases and abnormalities; for example, phantom limbs and chronic pain, usually cope with neuroplasticity. It can also explains about human echolocation in blind people, the effects of repeated use of brain-machine interface, and the results after mediation and physical exercise to cognitive improvement. Activity-dependent plasticity is the basis of memory formation.(2-3) In this case, neuronal activity, specifically the stimulation of neurons, changes gene expression and causes structural changes of neurons that may contribute to systematic changes. This is supported by the Hebbian theory that Neurons that fire together, wire together. Practice makes perfect is another prove to this kind of plasticity. It was first studied by Bach y Rita in blind people. Another scientist who mapped the organization of the brain in response to plasticity is Michael Merzenich. He also designed games and programs to help children with language-based impairment and autism. His programs promote the use of several cognitive regions therefore it stimulates other neurons to take place of the defected brain areas and to complete the tasks. One of his popular programs is Fast ForWord which helps children develop their phonological awareness. The activity of neuronal cells usually strengthens their connectivity, but this is not always true; sometimes they continue in the reverse. Spike-timing-dependent plasticity (STDP) explains how increased neuronal activity does not always strengthen neuronal connections. The strength of the connections is adjusted based on the level of the action potentials and their timing.(4-5) Here it coins the words long-term potentiation and long-term depression. The level of the action potentials, or the spikes, determines the connections of neurons when it is above the threshold. The timing of the spikes determines the connections of neurons by the time of potential inputs in relative to potential outputs. To say it simply, long-term potentiation is initiated when the
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input arrives before the output. In the other hand, long-term depression occurs when the input arrives after the output. The input here means the signals from the pre-synaptic neurons. It is experimentally considered at the pre-synaptic axon as the pre-synaptic spike. The output is considered to be the action potentials at the post-synaptic neurons. NMDA receptors are required for the output to occur. It may seem impossible for an output to be triggered before an input, but the outputs are usually found in neurons as they generate back-propagating action potentials. Here comes the Hebbian rule inaccurate. The neurons that fire together do not always wire together. They may quit wiring together if the firings are in bad timing. Plasticity is sometimes activity-independent.(6) The study by Bocchiaro and Feldman in 2004 showed the changes of AMPA receptors in cranial nerve XII motor neurons. They represented neuronal plasticity, but these changes did not result from the activities of AMPA receptors. They found that episodic applications of 5-HT2 receptor agonist to motoneurons increases AMPA receptor dive currents. The modulation here showed 5-HT-dependent postsynaptic potentiation of AMPA receptors. The possibilities to this phenomenon may be the convergent signaling cascades on phospholipase C, or may be direct receptor-receptor interaction. This result suggested that the plasticity of a particular type of receptor can be own activity-independent. The plasticity can exceptionally be mediated by the action of other types of neurotransmitter. Neuronal plasticity is usually considered as the changes of the ability of neuronal connection; this is synaptic plasticity. Synaptic plasticity involves the alteration of receptor number or efficiency at the post-synaptic neurons, or the quantity of neurotransmitter release from pre-synaptic neurons.(7-9) The mechanisms underlying synaptic plasticity were described previously as the results of NMDA and AMPA activities. During short-term
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synaptic plasticity, the activity of receptors changes by synaptic augmentation, a phenomenon that the release of neurotransmitter increases; synaptic depression, an event that the release of neurotransmitter decreases due to inhibitory pre-synaptic receptors; and neural facilitation or paired pulse facilitation, an event that post-synaptic potential increases because prior impulse is closely followed by another impulse. Short-term plasticity is said to be around 7 seconds. Unlike short-term plasticity, long-term plasticity lasts for more than minutes. There is more to do with the changes of chemical balance in post-synaptic neurons which may continue to manipulate gene expression. Synaptic plasticity is not specified to only the changes of receptors, but also includes the changes of extracellular matrix that connects the two neurons.(10) The overall changes to the connectivity have effects to the activity of the connected neurons, so called functional plasticity. The plasticity is not only found in synaptic clefts, it can also be found in the cell body and other areas of dendrites and axons. This is non-synaptic plasticity.(11-12) It usually involves the modification of voltage-gated ion channels in those sites. Non-synaptic plasticity may not play a big role on strengthening specific connections but it affects overall cellular excitability or inhibitory as well as synaptic integration. Synaptic plasticity and nonsynaptic plasticity are synergy. Non-synaptic plasticity at the axons, specifically at the voltage-gated ion channels at the nodes of Ranvier, can affect the latency in the propagation of EPSP along the axon and decreases the spike threshold. It then later increases the possibility to generate spikes and the excitatory potential therefore augments the release of neurotransmitters. Dendritic and somal non-synaptic plasticity helps increases the action potential, in this way it adds up the potential of synaptic plasticity. Connectivity strength can be saturated if neurons continue adding up their connections. To prevent the connectivity saturation, plasticity adjusts connectivity strength
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in relative to network activity. This is called homeostatic plasticity.(13-14) Without homeostatic plasticity, post-synaptic cells firing rate will increase after the strength of one connection increased. This will likely promote the other pre-synaptic cells to be more correlated with the post-synaptic activity. Later the post-synaptic neuron will lose its ability to transmit meaningful information. One mechanism to regulate firing rate is synaptic scaling. It is focused on the post-synaptic homeostasis of AMPA receptors which can be newly synthesized to the activated synapses within 4-5 hours after the activation. The more the synaptic connection is activated, the more AMPA receptors are added. One proposed mechanism that reverse the adding up of synaptic strength is via rectifying voltage-gated potassium channels. These potassium channels open in response to synaptic activations and allow potassium ions to move inward; therefore promote depolarization of the postsynaptic neuron and shorten the recovery time for the next activation. The most abundant rectifier potassium channel in the CNS is Kv2.1 channels which open early during the action potential cycle. However, the activation of NMDA receptors may allow calcium ion influx that triggers calcineurin, a calcium-calmodulin-dependent phosphatase and dephosphorylates Kv channels. (Figure 8.1) The dephosphorylated Kv channels are released from scaffolding proteins, freed from being clusters.
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Figure 8.1 Calcium entry through ionotropic glutamate NMDA receptors, voltage-dependent calcium channels (VCC) or intracellular calcium release activates calcineurin (PP2B), leading to the dephosphorylation and dispersal of Kv2.1 clusters.(15)
Neuronal plasticity is plastic itself. The plasticity changes depending on the neurons synaptic state. This is known as metaplasticity.(16-17) Factors that affect neuronal plasticity level include its activity, endocannabinoids, modulatory afferent neurons, and chemicals from glial cells or the gliotransmitters. The states can be active, potentiated, silent, or depressed. (Figure 8.2) The states can be judged by the amount of AMPA receptors which is related to the strength of memory. The endocannabinoid, 2-AG, released from postsynaptic neurons can also define the depressed state of pre-synaptic neuron metaplasticity. Glutamate, ATP and D-serine from astrocytes can modulate the activity of neurons. D-serine binds to glycine site of NMDA receptors and can induce NMDA-related neurotoxicity.
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Glutamate from astrocytes may trigger mGluR and kinate receptors to enhance neurotransmitter release from pre-synaptic neurons. Additionally, ATP can bind to postsynaptic P2X receptors and increases calcium ion level. Glutamate and ATP from astrocytes have synergic effect to the transition to active state of metaplasticity.
Figure 8.2 A model for state-dependent synaptic plasticity.(18)
Neurodegeneration may be considered to be the dark side event of neuroplasticity. It is the progressive loss of neuronal functions which is usually followed by the loss of neuronal structure. The primary factor of neurodegeneration is genetic abnormality which later projects to protein misfolding, protein aggregation, mitochondrial dysfunction, membrane damage, axonal transport disturbance, and programmed cell death.(19) One form of genetic mutation found in various diseases is the abnormal repetition of CAG. The disorders are known as Polyglutamine (PolyQ). This includes Huntingtons disease, Fragile X
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syndrome, Spinocerebellar ataxia, and Myotonic dystrophy. Other neurodegenerative disorders have polymorphisms in some specific genes. Protein misfolding is often exemplified as the aggregation of senuclein in Lewy bodies found in Parkinsons amyloid in disease, and hyperphosphorylated tau protein in neurofibrillary tangles and
senile plaques found in Alzheimer/s disease. Protein aggregation can be related to protein degrading enzymes complex, ubiquitin proteasome, which becomes less active. Excessive calcium ions from overactivation of neuron can trigger the release of cytochrome c from the inner membrane of mitochondria which later activates caspase 9 apoptotic pathways. Neuronal programmed cell death (PCD) is the death of neurons that is resulted from a cellular program. Loss of neuronal activation, limited nutrition supply, cellular stress, and physical or chemical damage can lead to PCD. Five common types of PCD have been discovered; apoptosis, autophagy, necrosis, necroptosis, and anoikis. Autophagy is a process the cells undergo as the machinery to maintain the balance of chemical and nutritional supply. It includes the lysosomal degradation of cells components. However, the process is not completely determines as the cause of cell death but rather found alongside with cell death. Necrosis is another PCD mechanism that usually does not trigger the immune response; therefore, the dead cells have to be removed surgically. It does not show stereotyped morphology and cannot be controlled because the transduction pathways are complex. The characters of necrosis are cytoplasmic swelling (oncosis), dilated organelles, and the loss of chromatin condensation. One programmed necrosis is called necroptosis. It is resulted from the activity of a receptor-interacting serine/threonine-protein kinase 1 (RIP1), which is inhibited by cytoprotective agent necrostatins. Another form of PCD is anoikis which is caused by the detachment of the cell from extracellular matrix. The disfunction of anoikis is found in turmor cell metastasis.
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Apoptosis is the most abundant form of PCD. The changes during apoptosis include chromatin condensation and fragmentation, nuclear and organelle fragmentation, and cell shrinkage and fragments (apoptotic bodies).(20) Apoptosis is less toxic when compared to necrosis since the apoptotic bodies can be engulfed and removed by phagocytic cells. Apoptosis can be triggered directly to the apoptotic pathways or indirectly to mitochondrial function. (Figure 8.3) One suggested pathway to apoptosis is via the tumor necrosis factor (TNF) receptors especially TNF-R1. The activation of TNF-R1 activates a membrane protein, TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD) which then induce caspase activity. Another theory suggests the activation through Fas receptors; Apo-1 or CD95, which initiate the formation of complex DISC. The complex comprises of FADD and some caspases. Apart from activating caspases, TNF pathway and Fas pathway can disrupt the balance between proapoptotic molecules (BAX, BAD, BAK, BID) and anti-apoptotic molecules (Bcl-2) on mitochondrial membrane.(21) Proapoptotic proteins can form complex of mitochondrial apoptosis-induced channel (MAC) on mitochondrial membrane. This will result as the release of cytochrome c (Cyt c) to cytosol which activates apoptotic protease activating factor-1 (Apaf-1). Apaf-1 can bind to procaspase 9 to form an apoptosome. The apoptosome in turn cleaves pro-caspase 9 to casepase 9 which activates caspase 3 just like the way the activator caspases (caspase 2, 8, 9, 10) proteolytically cleave inactivated effector caspases to become active. The effector caspases (caspase 3, 6, 7) once active can degrade intracellular proteins to dead by their proteolytic activities. The increase of mitochondrial membrane permeability also can be the result of nitric oxide. Then mitochondria swell and release apoptotic molecules. Small mitochondria-derived activator of caspases (SMAC) can be released from mitochondria and inactivate the inhibitor of apoptosis protein (IAP) by binding to it in the cytosol. IAP generally sequesters apoptotic molecules including caspases, but when it is inactive, the apoptotic
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pathways become disinhibited. Some scientists suggest a caspase-independent apoptosis pathway that starts from the damage of mitochondria. Mitochondrial membrane damage leads to the release of a mitochondrial inner membrane-anchored protein, apoptosis inducing factor (AIF). Its translocation to nucleus is resulted as chromatin condensation and DNA degradation.
Figure 8.3 The hierarchical network of mitochondrial QC mechanisms. Intramitochondrial proteases and molecular chaperone proteins maintain mitochondrial proteostasis.(21)
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The loss of neuronal cells or their parts are usually considered to have negative effects to learning and memory as seen in neurodegenerative disorders. Nevertheless, the process is found to be common during development and learning in the entire life. One critical topic of the event is neuronal pruning. Neuronal pruning is the process that the number of neurons or synapses is reduced. The result is not the malfunction of the neuronal activity but the efficiency.(22-24) The process is dramatically dominant after adolescent until adulthood. The removal of synapses and neuronal cells are believed to have beneficial purposes as it remove damaged or less important structures to improve the networking capacity of more essential structures. (Figure 8.4) Adults have 41% less neuronal cells than the newborn, but they have more synaptic connections. Some studies reported the dendritic pruning following the large increase of cytosolic calcium ion. Moderate rise in calcium ion elongates dendritic spine and formation of new spines, but the excessive rise of calcium ion causes fast shrinkage and the collapse of dendritic spines. One most common example for synaptic pruning is expressed through axon competition. The Use it or Lose it principle explains the survival of a particular synaptic connection when the synapse is frequently stimulated. This is due to the regulation by the post-synaptic neuron that increases synaptic protein to support connectivity and the supply of neurotrophic factors from glial cells as such that found in Wallerian degeneration. Axon stability is partly implicated by microtubule cytoskeleton stability which is in reverse to actin-myosin microfilament activity. One suggested pathway to axonal retraction is the activation of a small GTP-binding protein, RhoA. A downstream effector of RhoA is Rho kinase (Rok) which can phosphorylate myosin, hence promote axon retraction.
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Figure 8.4 Pruning cuts.(24)
Neuroregeneration is the repair mechanism after neurodegeneration. The central nervous system is not easily repaired compared to the peripheral. (Figure 8.5) Growth factors are limitedly expressed, and damaged tissues are slowly removed therefore glial scars develop rapidly and inhibit remyelination.(25) Transforming growth factors, interleukins, and cytokines upregulate the production of chondroitin sulfate proteoglycans (CSPG) and keratin sulfate proteoglycan (KSPG) from astrocytes. Other inhibitory proteins include Nogo A, oligodendrocyte myelin glycoprotein (OMgp) and myelin associated glycoprotein (MAG) through NgR1 receptor, repulsive guidance molecule A (RGM A) through neogenin receptor, ephrin B3 through EphA receptor, and semaphorins through neuropillin receptor and plexin receptor. These molecules inhibit neurite outgrowth via RhoRok pathway. To induce CNS regeneration, the inhibitory molecules, the receptors, or the pathway are attempted to be blocked. Experiments are ongoing and focusing on the treatment after spinal cord injury. Less evidence is found to study the effects to learning and memory in normal people.
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Figure 8.5 Diagram of human spinal cord injury. The primary injury site is usually small and secondary mechanisms such as excitotoxicity, inflammation and oedema formation contribute significantly to enlargement of the primary site of injury. An injured, transected and demyelinated nerve fibre is shown in the box. The transected nerve fibre expresses receptors for many neurite growth inhibitory proteins. Many of them activate the Rho-Rhokinase pathway leading to irreversible growth arrest of the injured fibre.(26)
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Neuronal stem cell is in a field of research and is being applied widely to neurodegenerative patients to replenish neuro-regeneration.(27-30) (Figure 8.6) The functions of stem cells are mainly to replace the lost neuronal cells or glia cells. The method is called cell replacement therapy. Moreover, the cells can be genetically modified for delivering drugs or synthesizing proteins that help improve the overall structure. It has been used successfully in animals with spinal cord injury by using neural cells induced from mesenchymal stem cells and a porous scaffold. Some studies have shown that injecting stem cells to the brain of mice can completely counteract the neural loss due to drug addiction.
Figure 8.6 The results so far obtained using NPCs as a therapeutic weapon for neurological disorders.(27)
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References
1. 2. 3. 4. 5. 6. Kercel SW. In memoriam: Paul Bach-y-Rita, MD, 1934-2006. J Integr Neurosci. 2007;6(4):v-vi. Spitzer NC. Activity-dependent neurotransmitter respecification. Nat Rev Neurosci. 2012;13(2):94-106. Rebola N, Srikumar BN, Mulle C. Activity-dependent synaptic plasticity of NMDA receptors. J Physiol. 2010;588(Pt 1):93-9. PMCID: 2821550. Letzkus JJ, Kampa BM, Stuart GJ. Does spike timing-dependent synaptic plasticity underlie memory formation? Clin Exp Pharmacol Physiol. 2007;34(10):1070-6. Tsodyks M. Spike-timing-dependent synaptic plasticity - the long road towards understanding neuronal mechanisms of learning and memory. Trends Neurosci. 2002;25(12):599-600. Bocchiaro CM, Feldman JL. Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons. Proc Natl Acad Sci U S A. 2004;101(12):4292-5. PMCID: 384734. Wang G, Grone B, Colas D, Appelbaum L, Mourrain P. Synaptic plasticity in sleep: learning, homeostasis and disease. Trends Neurosci. 2011;34(9):452-63. PMCID: 3385863. Gkogkas C, Sonenberg N, Costa-Mattioli M. Translational control mechanisms in long-lasting synaptic plasticity and memory. J Biol Chem. 2010;285(42):31913-7. PMCID: 2952191. Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat Rev Neurosci. 2010;11(10):675-81. Dityatev A, Schachner M, Sonderegger P. The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat Rev Neurosci. 2010;11(11):735-46. Hansel C, Linden DJ, D'Angelo E. Beyond parallel fiber LTD: the diversity of synaptic and nonsynaptic plasticity in the cerebellum. Nat Neurosci. 2001;4(5):467-75. Bach-y-Rita P, Illis LS. Spinal shock: possible role of receptor plasticity and non synaptic transmission. Paraplegia. 1993;31(2):82-7. Gordon GR, Bains JS. Can homeostatic circuits learn and remember? J Physiol. 2006;576(Pt 2):341-7. PMCID: 1890355. Perez-Otano I, Ehlers MD. Homeostatic plasticity and NMDA receptor trafficking. Trends Neurosci. 2005;28(5):229-38. Surmeier DJ, Foehring R. A mechanism for homeostatic plasticity. Nat Neurosci. 2004;7(7):6912.
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Abraham WC. Metaplasticity: Key Element in Memory and Learning? News Physiol Sci. 1999;14:85. Zorumski CF, Izumi Y. NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders. Neurosci Biobehav Rev. 2012;36(3):989-1000. PMCID: 3288588. Montgomery JM, Madison DV. Discrete synaptic states define a major mechanism of synapse plasticity. Trends Neurosci. 2004;27(12):744-50. Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci. 2004;22(7):507-14. Doi K. Mechanisms of neurotoxicity induced in the developing brain of mice and rats by DNAdamaging chemicals. J Toxicol Sci. 2011;36(6):695-712. Rugarli EI, Langer T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 2012;31(6):1336-49. PMCID: 3321185. Knoblauch A, Palm G, Sommer FT. Memory capacities for synaptic and structural plasticity. Neural Comput. 2010;22(2):289-341. Low LK, Cheng HJ. Axon pruning: an essential step underlying the developmental plasticity of neuronal connections. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1531-44. PMCID: 1664669. Wadsworth WG. Axon pruning: C. elegans makes the cut. Curr Biol. 2005;15(19):R796-8. Enciu AM, Nicolescu MI, Manole CG, Muresanu DF, Popescu LM, Popescu BO. Neuroregeneration in neurodegenerative disorders. BMC Neurol. 2011;11:75. PMCID: 3146817. Mueller BK, Mueller R, Schoemaker H. Stimulating neuroregeneration as a therapeutic drug approach for traumatic brain injury. Br J Pharmacol. 2009;157(5):675-85. PMCID: 2721253. Martino G. Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiology Review. 2011:1281-304. Wang S, Qu X, Zhao RC. Mesenchymal stem cells hold promise for regenerative medicine. Front Med. 2011;5(4):372-8. Yang N, Ng YH, Pang ZP, Sudhof TC, Wernig M. Induced neuronal cells: how to make and define a neuron. Cell Stem Cell. 2011;9(6):517-25. Lopez-Bendito G, Arlotta P. Cell replacement therapies for nervous system regeneration. Dev Neurobiol. 2012;72(2):145-52.
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Neuropathology/Psychiatry of Memory
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Chapter 9 Neuropathology/Psychiatry of Memory and Brain Aging

Akara Metasuk Neuropathology clarifies about the disease development, prevention and monitoring, and the treatment of diseases in the nervous system. There are a lot of diseases and disorders that are related to the defects in the nervous system. Some have basic etiology from genetic factors, some physical factors, some from chemicals or malnutrition, some from radiation, some from infections, etc. The neural responses in those etiologies are similar in many ways. Some disorders show sensorimotor functional abnormalities while others show cognitive abnormalities, or both. The abnormalities can be found in individual neurons or over the neural networks. Here in this chapter I will focus on substantial diseases and syndromes that have effects to the central nervous system, especially to learning and memory including Alzheimers disease, Parkinsons disease, Huntingtons disease, Picks disease, Creutzfeldt-Jacob disease, autism spectrum disorders, and most important, dementia and other mental disorders. The loss of cognitive abilities, including attention, memory, language, reasoning, and decision making, is determined as dementia.(1) Most brain-related neurodegenerative disorders express dementia as one of the pathology. Dementia can have early onset (occur before age 65) or late onset, static (such a result of brain injury) or progressive (in most diseases like AD), and reversible or irreversible depending on how the disorder is developed. Alzheimers disease (AD) is one most common feature of cognitive function disorders.(2-3) It cost 100,000,000,000 USD each year in the United States. At pre-dementia
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state of AD, the patient can have memory loss, apathy, and subtle problems in focusing attention, making plans, or thinking abstract. At the next level, the early state of AD, signs of agnosia, apraxia, and aphasia can be seen. Short-term memory is more affected than longterm memory. At moderate state of AD, paraphasia along with inabilities in reading and writing is found. Memory is worsening to the level that the patients may not recognize their close relatives. Long-term memory is highly affected. Behavioral changes can be dominant with aggression and resistance. Some patients may have delusions. Later in the advanced state of AD, speech is reduced to single words or absolute loss. Patients become completely dependent on caregivers even for simple tasks like feeding themselves. Because patients cannot do any tasks but only stay in bed, they usually die from pressure ulcers or pneumonia. AD structurally can be identified as the loss of neurons in the cerebral cortex. Amyloid plaques, or the insoluble amyloid peptide, and neurofibrillary tangles, or is a cut segment of a the aggregate of hyperphosphorylated microtubule-associated protein tau, are developed around or inside neuronal cells, respectively. (Figure 9.1) Amyloid transmembrane protein, amyloid precursor protein (APP). Senile plaques fromed by these abnormally cut proteins interfere calcium ion homeostasis and induce apoptosis. Normally phosphorylated tau protein stabilizes microtubule, but when hyperphosphorylated they become aggregated to one another, form tangles, and disrupt microtubule transport system. Most patients in AD have sporadic form of AD. Only 0.1% of them have familial form of autosomal dominant mutations in chromosome 21. The mutated genes include APP, presenilin 1, and presenilin 2. Presinilins are the proteins involved in the mutations increase the possibility to produce amyloid secretase intramembrane protease complex. The complex is crucial for the cleavage of APP. The 42 protein, rather than amyloid 40, which is the main component of senile plaques. Another genetic risk factor to AD is the
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possession of of amyloid
4 allele of apolipoprotein E (APOE). APOE generally enhances proteolysis , but APOE 4 has less ability in doing so. Apart from amyloid hypothesis
and tau hypothesis, cholinergic hypothesis states that AD is followed by the loss of acetylcholine neurotransmitter. However, treatment for this neurotransmitter is still ineffective.
Figure 9.1 Multifactorial Basis of Alzheimers Disease Pathogenesis.(2)
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Parkinsons disease (PD) causes motor symptoms at the central nervous system level due to the loss of dopaminergic cells in the substantia nigra and related areas.(4-5) It cost more than 10,000 USD/person at total cost of 230,000,000,000 USD each year in the United States. Late state of PD can develop cognitive function disabilities and some cellular components similar to AD. The first sign of PD is motor symptoms including 4-6 Hz tremor, increased muscle tone (rigidity), and slow movement (bradykinesia). Bradykinesia of PD is found to be slow movement of extremities from initiation to the completion. However, the motor disability state can be altered by emotional influence of the patients. Rigidity is usually initiated at the neck or shoulder. Postural instability can be developed in late state of PD. Patients become unable to set themselves to balance and fall frequently. In the advanced state of PD, cognitive ability, especially executive function, is affected. They have problems with making plans, thinking abstract, focusing attention, and maintaining cognitive speed. Memory recall is disrupted but can be recognized by cues. Behavioral alterations can be found with depression, apathy, anxiety, impulsivity, and hypersexuality. Some can experience hallucinations or delusions. Sensory loss and autonomic nervous system is also affected as having hypertension. Structural study of the brain can find the reduction of melanin pigmentation in the substantia nigra and locus coeruleus. Lewy bodies are the main histopathology in PD. Lewy body is formed by the accumulation of insoluble a few have genetic causes in synuclein protein that binds to ubiquitin and stay inside the cells. Most PD patients are sporadic. Only synuclein gene (SNCA), parkin (PRKN or PARK2), leucinerich repeat kinase 2 (LRRK2 or PARK8), PTEN-induced putative kinase 1 (PINK1), Parkinsons disease 7 (PARK7 or DJ-1), and probable cation-transporting ATPase 13A2 (ATP13A2). Synuclein normally is soluble and serves as a chaperone for the formation of
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SNARE complex which is essential for the kiss-and-run state of vesicle release. Its binding to lipid membrane also alters the membrane structure and promotes the formation of vesicles. Mutations or the multiplication of SNCA gene may contribute to the formation of beta structure of synuclein and promote to insoluble aggregate. PRKN mutation is another cause of PD. Parkin protein acts as the component of E3 ubiquitin ligase complex that degrades toxic proteins. Mutations in PRKN gene leads to the survival of toxic molecules that may cause the death of dopaminergic neurons. LRRK2 is also called as dardarin. It is a leucine-rich protein found at the mitochondrial outer membrane and interacts with parkin. PINK1 is less studied, but its expression products serine-threonine kinase activity protects the cell from stress-induced mitochondrial dysfunction. Similarly, DJ-1 is a peptidase and redox-sensitive chaperone that protects the cell from oxidative stress. The other genetic risk factor of PD is glucocerebrosidase (GCase) that hydrolyses glucocerebroside and prevents the cell from lipid accumulation. Huntingtons disease (HD) is related to the defects in muscle control and cognitive abilities. At the early state of HD, mild changes in physical and cognitive ability are found. The patients may develop random uncontrollable jerky movements (chorea) that finally disturb sleep. A few years later, rigidity or motor dysfunction can be developed. Difficulties in the control of facial muscles interfere facial expression, chewing, swallowing, and speaking. Executive functions are affected including planning and abstract thinking. Memory loss is progressive in almost all aspects from short-term memory, long-term memory, and working memory to episodic memory and procedural memory. Emotions can also be altered to anxiety, depression, and aggression.(6-8) HD have widespread effects to the whole brain but usually starts from substantia nigra, along with caudate nucleus and putamen in the neostriatum of the basal ganglia. Striatal spiny neurons are most affected. Genetics is the major cause of HD. The level of huntingtin gene (HTT) excessive CAG
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trinucleotide repeat or polyglutamine (PolyQ) determines the onset and the severity of HD. Htt is an anti-apoptotic agent and a regulator of vesicular transport and BDNF production. The polytrinucleotide repeats reduce Htt functions by leaving polar polyQ ends to extend. These polar ends cause the aggregation of Htt proteins and the formation of inclusions by their hydrogen bonds and interfere neuronal functions. (Figure 9.2)
Figure 9.2 Functional alterations in HD mitochondria.(6) Picks disease (PiD) is the loss of neuronal cells that mainly affects cognitive functions including aphasia, personality changes, and memory loss.(9-10) In the early state, patients can have problems about speech, and become passive or inert. The areas affected are known as frontotemporal lobar degeneration. Memory loss and aphasia can be found in later state of PiD. PiD symptoms are very close to AD, but the personality changes are found prior to memory loss, in contrast to AD that memory is found in the early onset. PiD patients
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develop hyperphosphorylated tau inside neuronal cells. These cells are called Pick cells. Pick cells altogether are stained and are seen as a dark stained aggregates called Pick bodies. Pick bodies, unlike neurofibrillary tangles in AD, are found in only specific areas. For example; layer 2 and 4 but not layer 3 and 5 of the cortex, the caudate, putamen, glubus pallidus, and locus ceruleus, but not the substantia nigra, are affected. Only a few isforms of phosphorylated tau protein are found in Pick bodies, in contrast to AD that can develop all six isoforms of tau. Creutzfeldt-Jakob disease (CJD) affects directly to motor disturbance including jerky movements (myoclonus) and ataxia. Patients can develop memory loss, behavioral changes and hallucination rapidly within weeks or a few months.(11-12) Death follows in six months or a few years because of the impaired coughing reflexes. Histological studies can find neuronal loss, gliosis, and many round vacuolization in the gray matter. Due to cell death, sponge-like appearance is shown in the brain tissue; so the disease called spongiform encephalopathies. The death of brain cells is the results of the formation of insoluble prion protein aggregates, amyloid plaques. CJD is similar to another transmissible spongiform encephalopathy, Gerstman-Strussler-Scheinker syndrome (GSS), but GSS does not always develop myoclonus. CJD can be familial by the inheritance of mutated prion protein gene (PRNP). Some cognitive impairment does not show severe structural changes of the brain, especially in the sensorimotor-related structures, but rather the imbalance of the chemical homeostasis. The personality and mood of the persons with the imbalance often draw associations to disabilities in social context and some aspects to cognitive abilities. These events are known as the results of mental disorders. However, some mental disorders
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should not be considered as illness since the borderline between the being mental disorder and mental normality is not clear depending on social judgment. Autism spectrum disorders (ASD) are vast conditions of mental disabilities resulting from developmental disorders. Difficulties in social development, communication, and repetitive behaviors are found in all ASDs, but different types of disorders can develop the deficits in different levels.(13-18) There are 3 common types; autism, Asperger syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). ASD patients can have neuronal growth reduction in some areas but enlargement in the other areas of the brain. This happens because of the abnormalities of pruning and growth in the early stage of the brain development. The affected areas are composed of frontal lobe, limbic system, temporal lobe, and corpus callosum. The activity of the mirror neuron system (the inferior frontal gyrus and inferior parietal lobe) is also limited. Mental retardation can be seen in some ASD, but this may not be the effect of abnormal brain development. Since ASD is not the majority of children, usual learning styles may not be suitable for ASD patients and therefore do not promote effective learning for them. Autism has impaired social interaction, impaired communication, and repetitive behavior. These abnormalities are clearly seen before the child enters his/her 3rd year. Impaired social interaction is shown by the lack of attention to emotional facial expressions, and can hardly imitate those expressions. Children with autism have less eye contact and communicate with less nonverbal techniques. The quality, but not quantity, of friendship is still important for them. Verbal communication is delayed. Repetitive behavior can be expressed with different scales ranging from stereotypic movement, compulsivity or intention to follow rules, resistance to change, and self injury. These disorders may be the results of excessive neurons or overconnectivity, unbalanced excitatory-inhibitory networks,
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or abnormal synaptic formation. Asperger syndrome shares the same characteristics in autism, but it does not show delayed language and cognitive development. However, restricted interest is strongly associated to this syndrome. The other disorders that have difficulties in social interaction and communication are categorized in PDD-NOS. There is an unavoidable memory-declining event that all of us are experiencing. It is brain aging. When people get older, they are more susceptible to neurodegenerative diseases and dementia.(19-21) The overall dendritic structure is not affected but the dendritic spine density is significantly reduced. (Figure 9.3) The most studied implications to the improper processing of memory are the accumulated oxidative stress. It damages functional proteins, cell structure and DNA therefore can result as the neuronal cell malfunction, loss of plasticity and neuronal death. The structural decrease of gray matter and white matter volume follows. There is a decrease of neurotransmitter receptors including dopamine D1, D2, D3, serotonin 5-HT2, and glutamate receptors. Most of the types of memory are affected including long-term memory, episodic memory, semantic memory, short-term memory and working memory. Some other causes may be the less efficient or any clotting in the cerebrovascular system. Some scientists suggested that the delay in learning may come from having too much information. It may slower memory processing and dampens the ability to focus attention. Attention is the key in working memory to shortterm and long-term memory. This may be true since the defect in attention can have broad effects to all kinds of explicit memory. Some studies suggested effects of the role of circadian clock to aging by regulating the metabolism and the reactive oxygen species homeostasis. (Figure 9.4)
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Figure 9.3 Basic mechanism of NMDA receptordependent postsynaptic long-term potentiation (LTP). Right panel depicts the events in a synapse impaired by aging.(20)
Figure 9.4 Potential mechanisms of circadian clock-dependent regulation of neurodegeneration.(19) Neurodegenerative disorders stated above are somewhat have effects to memory directly by their pathology in memory-related brain structures. However, some of them have only mild or no conditions of memory impairment. The reason behind the level of impairment
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is due to the level of structural destruction that has effects to the disruption of neuronal connectivity. Some of the disorders have indirect effect to memory since the main structure of memory is not affected, such as schizophrenia, obcessive-compulsive disorder, anxiety disorder, bipolar disorder, dissociative disorders, depressive disorder, and perfectionism. However, there are always some effects in one or another way that draw from other symptoms. For example; sleep disturbance, attention deficits, mental stress, and difficulty in consumption may have effects to the quality of life which sum up to affect various processes of memory, from encoding to consolidation. Living without diseases is still the best to all mankind, at least in the aspects of memory. Aging is one simple thing that anyone can hardly avoid, but the effects of aging to memory can be reduced or even improved by recreational drugs and activities to be discussed in chapter 10-11.
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References
1. 2. 3. 4. 5. Paulson HL, Igo I. Genetics of dementia. Semin Neurol. 2011;31(5):449-60. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):120422. PMCID: 3319071. Tam JH, Pasternak SH. Amyloid and Alzheimer's disease: inside and out. Can J Neurol Sci. 2012;39(3):286-98. Schwartz M, Sabetay S. An approach to the continuous dopaminergic stimulation in Parkinson's disease. Isr Med Assoc J. 2012;14(3):175-9. Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease. Cochrane Database Syst Rev. 2012;3:CD006504. Costa V, Scorrano L. Shaping the role of mitochondria in the pathogenesis of Huntington's disease. EMBO J. 2012;31(8):1853-64. PMCID: 3343341. Ehrnhoefer DE, Wong BK, Hayden MR. Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development. Nat Rev Drug Discov. 2011;10(11):853-67. PMCID: 3206090. Raymond LA, Andre VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS. Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 2011;198:252-73. PMCID: 3221774. Hornberger M, Piguet O. Episodic memory in frontotemporal dementia: a critical review. Brain. 2012;135(Pt 3):678-92. Kertesz A, McMonagle P, Jesso S. Extrapyramidal syndromes in frontotemporal degeneration. J Mol Neurosci. 2011;45(3):336-42. Haik S, Brandel JP. Biochemical and strain properties of CJD prions: complexity versus simplicity. J Neurochem. 2011;119(2):251-61. Lloyd S, Mead S, Collinge J. Genetics of prion disease. Top Curr Chem. 2011;305:1-22. Marshall CR, Scherer SW. Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol Biol. 2012;838:115-35. State MW, Levitt P. The conundrums of understanding genetic risks for autism spectrum disorders. Nat Neurosci. 2011;14(12):1499-506.
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8.
9. 10. 11. 12. 13. 14.
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Philip RC, Dauvermann MR, Whalley HC, Baynham K, Lawrie SM, Stanfield AC. A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders. Neurosci Biobehav Rev. 2012;36(2):901-42. Holtmann M, Steiner S, Hohmann S, Poustka L, Banaschewski T, Bolte S. Neurofeedback in autism spectrum disorders. Dev Med Child Neurol. 2011;53(11):986-93. Choudhury PR, Lahiri S, Rajamma U. Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacol Biochem Behav. 2012;100(4):841-9. Holt R, Monaco AP. Links between genetics and pathophysiology in the autism spectrum disorders. EMBO Mol Med. 2011;3(8):438-50. Kondratova AA, Kondratov RV. The circadian clock and pathology of the ageing brain. Nat Rev Neurosci. 2012;13(5):325-35. Deak F, Sonntag WE. Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1. J Gerontol A Biol Sci Med Sci. 2012;67(6):611-25. PMCID: 3348499. Morrison JH, Baxter MG. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci. 2012;13(4):240-50.
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Drug Addiction and Memory
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Chapter 10 Drug Addiction and Memory

Akara Metasuk The network of neurons is regulated by electrochemical connections. Imbalance of chemicals in the brain can have effects to memory. The use of drugs can alter the chemical components of the brain. Most of the drugs of abuse have been used in clinical treatments, but nowadays it becomes illegal to have those drugs without clinician prescription. Drug abuse is one major problem in all countries. It leads to society problems that lower quality of life including criminals and disease dispersals. Drugs can modulate learning and memory and other cognitive functions in both positive and negative aspects, whether in short- or long-term.(1) Some are beneficial but can show negative symptoms and dependency when repeatedly used. (Figure 10.1) Here I will focus on the effects to memory of some wellknown drugs of abuse and chemicals though are not considered as drugs of abuse but have some, not strong but a little, addictive effect. One of the most well-known and most problematic drugs of abuse is amphetamine. It is the parent compound of N-methylamphetamine (methamphetamine) and 3,4methylenedioxy-N-methamphetamine (MDMA). Its effects include wakefulness, concentration, self confident, aggression, anxiety, increased blood pressure, and decreased fatigue and appetite. Amphetamine can modulate the effects of various neurotransmitters but the main regulation is on dopamine D2 receptors in the hippocampus, striatum, nucleus accumbens and ventral striatum. It enters neuronal cells via monoamine transporters (MAT); DAT, SERT, and NET. Amphetamine can be uptaken into vesicles by vesicular monoamine trasporter 2 (VMAT2) and promote the release of dopamine to cytosol by reducing hydrogen ions in the vesicles because amphetamine itself is a weak base. Then
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the increased concentration of dopamine in cytosol induces the release of dopamine to synaptic clefts by reversing the activity of dopamine transporter (DAT). Amphetamine may also act on protein kinase C(PKC- ) to phosphorylate DAT. Phosphorylated DAT then reverse its normal activity. Others activity of amphetamine to dopaminergic system include the inhition of monoamine oxidase (MAO), an enzyme that breaks down cytosolic dopamine, and the enhancing of tyrosine hydroxylase (TH), an enzyme responsible for the production of L-DOPA, a dopamine precursor. Amphetamine exerts its effect on serotonin transporter (SERT) the way similar to DAT. The increased synaptic serotonin later may augment the effect of excitatory glutamatergic neurons. Extracellular glutamate and norepinephrine are also found to be increased. Amphetamine shows to have positive effects to memory since it increases attention and alertness, but the overuse of amphetamine can induce toxicity and neural cell death since cytosolic monoamines, specifically dopamine, can be metabolized to have oxidizing activity and induce oxidative stress.(2-4) Thats why amphetamine is not suitable for long-term performance-enhancing use. Methamphetamine and MDMA act similarly to amphetamine. Methamphetamine is metabolized from amphetamine, but it is more potent and rapidly crosses blood-brain barrier because of its lipophilicity. MDMA or ecstasy acts more on serotonergic system therefore it induces more euphoria and is less addictive than amphetamine. Under exposure to MDMA, oxytocin level and ventromedial prefrontal activity are increased while amygdala activity decreases.(5-6) This suggests how MDMA decreases avoidance and improves emotional engagement. Drugs in opioid group are derived from opium poppy. They mimic endorphins by binding to opioid receptors , , and . They give analgesic effects with
2 1
and
receptors, sedative effects with
receptor, and physical dependence by
receptor.
They were used as pain suppressor (analgesics) in the history but they also induce euphoria
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and, fatally, respiratory depression. Opiates or alkaloids from opium are extracted and modified in various forms including morphine, codeine, and heroin. Morphine has been used as universal analgesic for long time, but its lipid solubility is very low that can hardly cross blood-brain barrier. A chemically modified form of morphine is diacetylmorphine or heroin. It has higher lipophilicity, so it is more potent than morphine, but once entered the brain heroin has to transform to morphine to burst the effects. 3-Methylmorphine or codeine is a popular opioid widely used as analgesics second to morphine. It has wider bioavailability and less potent than morphine, so physicians can adjust the range for drug dose easily. Likewise, codeine is metabolized to morphine before taking the effects, but the conversion is processed in the liver. Since these chemicals are depressants, they suppress cognitive abilities. They impair attention and memory, both anterograde and retrograde.(7-8) Marijuana is the dried flowers and leaves of cannabis plant. It is used as antidepressant, reducing nausea, and increasing appetite in AIDS and cancer patients during chemotherapy. Euphoria comes from the active chemical in cannabis is tetrahydrocannabinol (
9
-9-
-THC or THC). It is a partial agonist of cannabinoid receptor CB1
in the brain. THC has antioxidant activity that may protect neurons. Moreover, it has anticholinesterase activity that may partly help patients with Alzheimers disease. However, its short-term effects on memory are unpleasing because it limits working memory and short-term memory. No fatality has been founded to be related to using cannabis.(9) Inhalants are not exactly drugs of abuse but they are usually misused home chemicals. The most common inhalants are nitrous oxide and toluene. Nitrous oxide or laughing gas, an analgesic gas used in dentistry, is an NMDA receptor antagonist and GABAA receptor enhancer. It gives anesthetic, analgesic, anxiolytic, and euphoric effects by activating dopaminergic neurons in ventral tegmental area and nucleus accumbens. It is
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beneficial by inhibiting glutamate-induced excitotoxicity, but instead its NMDA antagonist activity can induce NMDA receptor antagonist neuotoxicity (NAN or Olneys lesions) after long-term usage.(10-11) Toluene is an organic solvent in paint thinners, adhesives, and lacquers. It is an NMDA antagonist and GABAA receptor modulator that induce euphoric effect just like nitrous oxide. It can cause confusion and memory loss after exposure. Unconsciousness may be experienced with high dose of toluene.(12-13) Hallucinogens are compounds that induce perceptions to differ from what is perceived in consciousness. Lysergic acid diethylamide (LSD) is an example. Its effects are on G protein-coupled receptors for dopamine and serotonin. LSD has low affinity to 5-HT1A, 5-HT2A, 5-HT5A, 5-HT2C, and 5-HT6 receptors. It is believed that LSD may affect the perception by enhance the release of glutamate in the cortex. It may have negative effects to memory and attention because it induces confusion and impairs decision making.(14-15) Cocaine or benzoylmethylecgonine is an alkaloid produced from coca plant. Its hydrophilicity and lipophilicity are in the range that allows the molecule to be bransported in blood and pass blood-brain barrier efficiently. It interferes the reuptake mechanism of dopamine, serotonin, and norepinephrine. Cocaine induces euphoria and alertness by binding to DAT and blocks the transporter activity in ventral tegmental area, nucleus accumbens, and prefrontal cortex. Local anesthetic effect of cocaine comes from the blockage of sodium channels. This leads to the disruption of action potentials. Chronic use of cocaine can decrease the signaling and show depressive mood.(16-19) Nicotine is also an alkaloid but is found in tobacco. Cigarettes with menthol can extend the half-life of nicotine which is normally 2-3 hours because menthol inhibits the metabolism that destroys nicotine. Nicotine has stimulant effects by acting directly on nicotinic acetylcholine receptors, increasing the dopaminergic activity for euphoria. Other
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compounds in tobacco that support nicotine effects are harman and norharman. They decrease monoamine oxidase (MAO) which normally breaks down dopamine, serotonin, and norepinephrine. Benefits of nicotine to memory, concentration, and alertness are provided by the enhanced activity of acetylcholine. At low dose, nicotine has effects to norepinephrine and dopamine for alertness, but at high does it has effects on serotonin and opioid systems which produce mild sedative and calming effects.(20-22) The addiction of tobacco does not come from nicotine but from MAOI activity of harman. Ethyl alcohol or ethanol causes 10% of dementia. It inhibits the binding of glutamate to NMDA receptors and stimulates GABAA receptors throughout the brain and causes overall system depression.(23-24) Alcohol also modulates the receptors at expression level by decreasing dopamine D2 receptor in the striatum and decreasing the phosphorylation of NMDA receptor 2B subunit in the prefrontal cortex, hippocampus, and nucleus accumbens. Very low dose of alcohol can induce euphoria, sociability, and lowered inhibition, but higher dose can result as stupor, sedation, confusion, ataxia, and unconsciousness. Blacking out or anterograde amnesia is one common result of drinking excessive dose of alcohol. Moderate consumption of alcohol at 30-60 minutes before going to bed suppresses rapid eye movement stage (REM) and speeds up slow wave sleep (SWS) in the first 4 hours of sleep, and then it increases REM later in hour 5-8. The disruption of sleep architecture may impair memory. Low dose of alcohol can, on the other hand, improve sleep maintenance. This may be a good choice for insomniacs. However, chronic consumption of alcohol will turn NMDA receptors to be upregulated. This is why abstinence can induce excitotoxicity apoptosis, resulting in severe cognitive impairment, hallucinations, and possible seizures. Apoptosis may also be activated long-term alcohol exposure via a neuroinflammatory pathway. Alcohol induces the phosphorylation of IL-1R-associated kinase (IRAK), c-Jun Nterminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) which in turn
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stimulate NF- B and AP-1 transcription factors to express iNOS and COX-2. These chemicals trigger caspase 3 resulting to apoptosis. A genetic risk factor to alcoholism is alcohol dehydrogenase ADH1 B*3 that was proposed to have rapid metabolism for degradation of alcohol. This allele is found in native African and native American.
Figure 10.1 Neural circuits reorganization after drug exposure. Synaptic connection of a number of interconnected regions where DA neuromodulation plays a crucial role, are susceptible to drug exposure.(1) It can be said that the most frequently consumed neuromodulatory chemical is caffeine. It is an alkaloid from coffee, tea, and soft drinks. It reduces fatigue and drowsiness and increases attention and alertness.(25-27) Overdose of caffeine is related to anxiety and insomnia. After crossing blood-brain barrier, caffeine increases dopamine and glutamate activity, therefore lowers the activation threshold, in cerebral cortex and hippocampus by its antagonistic activity on adenosine A2A receptor. A2A receptor is a G protein-coupled receptor
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that results as disruption of synaptic vesicle release and the stabilization of magnesium on NMDA receptors. Caffeine also enhances the activity of acetylcholine by inhibiting acetylcholinesterase. Experiments on short-term memory and working memory are still controversial, but the results of caffeine to long-term memory are shown to be positive. Consumption of caffeine before performing a task does not show any effects, but consumption at low dose after the task shows to be beneficial. Consumption of caffeine can be addictive. Withdrawal symptoms include headache, nausea, and depressive mood. Drugs of abuse are socially considered to be evil, but some evidences have shown that they have beneficial modulatory effects to cognitive functions in certain conditions. Nevertheless, the use of some of these drugs may have to be under control of clinicians, otherwise would be illegal. Next I will give more information about other modulatory chemicals and activities not limited to only drugs of abuse.
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References
1. 2. 3. 4. 5. 6. 7. 8. 9. Mameli M, Luscher C. Synaptic plasticity and addiction: learning mechanisms gone awry. Neuropharmacology. 2011;61(7):1052-9. Meredith CW, Jaffe C, Ang-Lee K, Saxon AJ. Implications of chronic methamphetamine use: a literature review. Harv Rev Psychiatry. 2005;13(3):141-54. Scott JC, Woods SP, Matt GE, Meyer RA, Heaton RK, Atkinson JH, et al. Neurocognitive effects of methamphetamine: a critical review and meta-analysis. Neuropsychol Rev. 2007;17(3):275-97. Marshall JF, Belcher AM, Feinstein EM, O'Dell SJ. Methamphetamine-induced neural and cognitive changes in rodents. Addiction. 2007;102 Suppl 1:61-9. Zakzanis KK, Campbell Z, Jovanovski D. The neuropsychology of ecstasy (MDMA) use: a quantitative review. Hum Psychopharmacol. 2007;22(7):427-35. Kalechstein AD, De La Garza R, 2nd, Mahoney JJ, 3rd, Fantegrossi WE, Newton TF. MDMA use and neurocognition: a meta-analytic review. Psychopharmacology (Berl). 2007;189(4):531-7. Dacher M, Nugent FS. Opiates and plasticity. Neuropharmacology. 2011;61(7):1088-96. Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol. 2008;154(2):384-96. PMCID: 2442443. Lundqvist T. Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions. Pharmacol Biochem Behav. 2005;81(2):319-30. Bank HSD. Nitrous Oxide [cited 2012 23 July]: Available from: http://toxnet.nlm.nih.gov/cgibin/sis/search/r?dbs+hsdb:@term+@rn+10024-97-2. Duarte R, McNeill A, Drummond G, Tiplady B. Comparison of the sedative, cognitive, and analgesic effects of nitrous oxide, sevoflurane, and ethanol. Br J Anaesth. 2008;100(2):203-10. Huerta-Rivas A, Lopez-Rubalcava C, Sanchez-Serrano SL, Valdez-Tapia M, Lamas M, Cruz SL. Toluene impairs learning and memory, has antinociceptive effects, and modifies histone acetylation in the dentate gyrus of adolescent and adult rats. Pharmacol Biochem Behav. 2012;102(1):48-57. Yucel M, Takagi M, Walterfang M, Lubman DI. Toluene misuse and long-term harms: a systematic review of the neuropsychological and neuroimaging literature. Neurosci Biobehav Rev. 2008;32(5):910-26. Appel JB, West WB, Buggy J. LSD, 5-HT (serotonin), and the evolution of a behavioral assay. Neurosci Biobehav Rev. 2004;27(8):693-701.
10. 11. 12.
13.
14.
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15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther. 2008;14(4):295-314. Chae SM, Covington CY. Biobehavioral outcomes in adolescents and young adults prenatally exposed to cocaine: evidence from animal models. Biol Res Nurs. 2009;10(4):318-30. Williams MJ, Adinoff B. The role of acetylcholine in cocaine addiction. Neuropsychopharmacology. 2008;33(8):1779-97. PMCID: 2667818. Garavan H, Hester R. The role of cognitive control in cocaine dependence. Neuropsychol Rev. 2007;17(3):337-45. Harvey JA. Cocaine effects on the developing brain: current status. Neurosci Biobehav Rev. 2004;27(8):751-64. Swan GE, Lessov-Schlaggar CN. The effects of tobacco smoke and nicotine on cognition and the brain. Neuropsychol Rev. 2007;17(3):259-73. Aubin HJ, Rollema H, Svensson TH, Winterer G. Smoking, quitting, and psychiatric disease: a review. Neurosci Biobehav Rev. 2012;36(1):271-84. Herman AI, Sofuoglu M. Cognitive effects of nicotine: genetic moderators. Addict Biol. 2010;15(3):250-65. PMCID: 2903639. Lee H, Roh S, Kim DJ. Alcohol-induced blackout. Int J Environ Res Public Health. 2009;6(11):2783-92. PMCID: 2800062. McCool BA. Ethanol modulation of synaptic plasticity. Neuropharmacology. 2011;61(7):1097108. PMCID: 3149748. Nehlig A. Is caffeine a cognitive enhancer? J Alzheimers Dis. 2010;20 Suppl 1:S85-94. Biessels GJ. Caffeine, diabetes, cognition, and dementia. J Alzheimers Dis. 2010;20 Suppl 1:S143-50. Gardner EJ, Ruxton CH, Leeds AR. Black tea--helpful or harmful? A review of the evidence. Eur J Clin Nutr. 2007;61(1):3-18.
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Medicines, Chemicals and Activities
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Chapter 11 Medicines, Chemicals and Activities for Memory Booster, Memory Alteration and Memory Clearance
Akara Metasuk Normal people frequently have some problems with their memory; unable to remember the details during studying or in the meetings, unable to recall the names of important people or customers, having to try very hard in getting used to vocabularies of a foreign language, or unable to forget what an ex-boyfriend/girlfriend has done badly. The problems are considered when they cannot be remembered, recalled, or removed. Some people may also have problems when memories are unorganized, in other words they have confusion about what is real and what is imagined. Before looking deeper into those problems, it might be a profitable chance to consider how memory-related diseases are treated. After that, I will introduce some medicines, food, and activities that are proposed to produce beneficial results to memory. Dementia shows defects in various cognitive functions. The management of dementia depends on the symptoms that the patients experience. There is still no cure, but the most popular treatment is cholinesterase inhibitors and cognitive-behavioral therapy. Acetylcholinesterase inhibitors being used today for patients with Alzheimers disease or Parkinsons disease include tacrine, donepezil, galantamine, and rivastigmine.(1-2) Oral or transdermal therapeutic dose of acetylcholinesterase inhibitors can cause many adverse reactions; nausea, vomiting, bradycardia, hypotention, diarrhea, and hepatotoxicity. The efficiency of these chemicals is still controversial since some studies showed that they can improve cognitive impairments even in severe patients, especially donepezil; but some
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studies did not find any difference to the control group. Whatever reason, acetylcholinesterase inhibitors are still not the effective method to reverse or stop the symptoms of dementia and Alzheimers disease. Another medicine that, instead of increasing acetylcholine, increases the signal-to-noise ratio of glutamate system is memantine. It is an NMDA receptor antagonist that also prevents excitotoxicity.(3) NMDA receptor blocker, memantine, is another option that can be given together with acetylcholinesterase inhibitors. Memantine can give adverse effects too, but the body usually tolerates this chemical well. Possible reactions are confusion, headache, insomnia, and hallucination. Cognitive flexibility may be affected. Memantine is also an antagonist of 5HT3 receptor, acetylcholine acetylcholine -7 nAChR, and dopamine D2 receptor. Early blockage of -7 nAChR can contribute to the worsening of cognitive impairment, but
once the receptors are upregulated, the results can reveal as cognitive enhancing. There is a chemical that acts as both acetylcholinesterase inhibitor and as an NMDA antagonist. It is Huperzine A. ZT-1, being under drug development, is the pro-drug of this chemical. It is very well tolerated therefore hardly induce adverse effects. It is sold as a dietary supplement and can be found in Huperzia plants. Not only in patients, can normal people also improve their cognitive abilities by exercising the brain with appropriate environments. All of these factors have effects to cognition by modulating neuronal plasticity. Some chemicals have been developed to improve memory. They are called cognitive enhancers. Some cognitive enhancers are less toxic. They are known as nootropics. A traditional plant for enhancing cognition is Ginkgo biloba. Some studies showed that Ginkgo improves attention in normal people, but the results to cognition are still under debate. Some chemicals show beneficial effects to memory, but they are illegal or have potent harm, such as tetrahydrocannabinol (THC),
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amphetamine, 4-ethylaminorex, entheogens, methylenedioxypyrovalerone (MDPV), and nicotine. Some nootropics are in racetam class, a group of chemicals that have 2pyroolidone ring. They bind to specific receptors and modulate the activity of neuronal cells. For example; piracetam may act on ion channels and increase synaptic excitability, whether in inhibitory or excitatory synapses. Its activity on acetylcholine system and glutamate system can be responsible for memory functions. Interestingly it does not have effects to GABA receptors. Some chemicals do not act on neurotransmitter receptors but may enhance memory via increasing blood flow; creatine, coenzyme Q-10, and vinpocetine, and some promotes neuroprotection; melatonin and glutathione.(4) Apart from medicines, other environmental factors take roles in memory abilities every day. There are some developed techniques proved to enhance memory processing. They involve a variety of mnemonic principles and coined as the art of memory.(5) The most common principle is to attach any information with visual sense, meaning that when hearing, smelling, eating, or touching something, seeing or imagining the visual appearance will enhance the memory about the information. The idea supports the principle of setting the visual information or other perceptions in order because ones virtual space is already represented as series of order. Associating information to the other can increase the possibility to remember that set of information. Thinking visually and orderly can help increase memory performance, but it may not work properly if there is too much information in the roll. Chunking is a technique that long series of information are divided or grouped. The groups are separately remembered one at a time. It works consistently by the serial position effect; the primacy effect and the recency effect, which reveals that the first few items and last few items are frequently remembered than the middle items, and starting recall from the end of the list shows better recall than starting from the beginning. Repetition makes perfect is still true in the art of memory. The idea goes along with the
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forgetting curve that shows exponential memory decline after the exposure to the information. Hermann Ebbinghaus proposed an equation describing the forgetting curve as:
Equation 11.1 where R is memory retention, e is 2.71828, t is time, and S is the relative strength of memory.(6-8) Another principle to enhance memory is to add affection into the information. Emotion may work as increasing visual sense to the information or may strengthen memory by itself. This is described as Von Restorff effect which explains that isolating item by attention can enhance memory.(9) The way in which one perceives the information also affects the performance of memory. Textual mnemonic suggests that thinking textually increases memory. An example for this is reading out loud rather than reading quiet. Graphical mnemonic, on the other hand, suggests adding signs or symbols that creates visual clues for the information. It may work by simplifying the information, the same way as chunking works. Architectural mnemonic lets the information to be manipulated into one picture or a series of pictures. The popular tool in this mnemonic is the method of loci. If remembering numbers, this method can be adapted to use with mnemonic major system or mnemonic dominic system that numbers are transformed to alphabets using associated consonants. These alphabets are used to create words of people names, objects, or actions. To increase the performance of memory can also be modulated at the retrieval level. Encoding specificity explains that the recall of memory is performed better in the situation specific or similar to the situation during encoding. Exercise, food, and rest are the main factors to shape how a person has a healthy body, so does the healthy brain. (Effects of sleep is described in Figure 11.1 and Chapter 4)
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Food not only supports the cognitive functions by providing energy and building blocks for protein sysnthesis but also modulates cellular activities by means of structure and chemical performance. Moderate level of glucose empowers metabolism, but low level or excessive level of glucose can impair memory.(10-11) Vitamin B1 (thiamine) affects the function of nervous system due to its coenzyme activity that metabolizes carbohydrates for the usage of glucose.(12) Saturated fat, cholesterol, and high caloric intake are negative factors that promote working memory errors and Alzheimers disease.(13) Polyunsaturated fats compose of polyunsaturated fatty acids (PUFA).(14) Docosahexaenoic acid (DHA), an Omega-3 fatty acid is related to cognitive improvement and is the building block of the gray matter. Omega-6 fatty acid, in opposite, interferes with Omega-3 fatty acids. The ratio of dietary Omega-6 to Omega-3 should be 4:1 or less. Cholesterol in cell membrane can reduce the membrane fluidity and permeability. However, its function on the packing of plasma membrane of myelin sheath provides efficient insulation for better nerve conduction.(15) Vitamin B3 (niacin) is related to cognitive function because it is required for the synthesis of fatty acids and cholesterol.(16) Flavonoids in a variety of vegetables and fruits counteract with oxidative stress and promote neurogenesis.(17-19) Good sources of flavonoids are broccoli (flavonols), celery (flavones), soy bean (isoflavones), berry (anthocyanidins), tomatoes and citrus (flavanones), and cocoa, red wine, and green tea (flavanols). Choline is a substrate for the synthesis of acetylcholine. It was shown that choline intake can reduce the number of times of learning, decrease age-related memory loss, and slightly reverse memory impairment in Alzheimers disease.(20-22) Sources of choline involve liver, eggs, milk, and peanuts. Vitamin A (retinol and carotenes) is related to cell division and gene transcription. Vitamin A deficiency brings about spatial memory impairment since the most affected brain area is the hippocampus.(23-24) Zinc deficiency also has similar effects to vitamin A because it balances vitamin A plasma level.(25) Vitamin
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B9 (folic acid) and vitamin B12 (cobalamin) are required for the synthesis of S-adenosyl methionine (SAM) which is related to methyl group transfer and neuronal cell repair.(26) Aerobic physical exercise has shown to be beneficial to memory. It regulates hippocampal neurogenesis and the expression level of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor (TrkB), a receptor for BDNF. BDNF and TrkB are related to synaptic plasticity and repair.(27-28) Insulin growth factor 1 (IGF-1) is also increased during exercise. It is the main activator of AKT pathway which is related to cell proliferation and the inhibition of programmed cell death. Exercises improve cardiovascular system therefore promotes oxygen and nutrition supply. The characteristics of the exercise itself can also train cognition because exercises or sports usually require planning, multitasking, and working memory. The immediate or short-term results that can be experienced during or after doing physical exercises can be an increased in oxygen, glucose, and nutrients delivery to the brain. The benefits are limited to aerobic exercises and not anaerobic exercises. Endorphins released from the pituitary during exercise together with the distraction from stress inducers can reduce stress which is related to cortisol. Cortisol, after released from adrenal gland, can induce hippocampal neurodegeneration and then shuts down the negative feedback loop of hippocampus to hypothalamus. Moderate exercises can induce mild cortisol release which increases threshold for the release of cortisol. Additionally, exercise regulates the balance of neurotransmitters; it stabilizes the level of dopamine D2 receptor, increases dopamine levels that in turn modulate the glutamate memory system especially attention, and elevates serotonin synthesis that directly is related to the retrieval of short-term memory and the expression of BDNF. Norepinephrine, the fight-or-flight hormone, released with the challenges in the sports or games is related to attention. Long-term effects of exercise can be the structural increase of gray matter volume of the dorsolateral prefrontal cortex, an area for the formation of long-term memory; anterior
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prefrontal cortex, related to the verification of memory; anterior cingulated cortex, related to problem solving and processing of emotional content; and posterior cingulated cortex, related to episodic recognition. Some studies have interestingly shown that physical exercises reduce the chance or slow the progression of neurodegenerative disorders including Alzheimers disease, Parkinsons disease, and Huntingtons disease. Mental exercises or performing tasks that require cognition can serve as positive factors to memory and delays cognitive disorders such as Alzheimers disease. The benefits of music training and mental exercise are related to the characteristics of the exercise. A regular mental exercise is music playing. It shows that participation in music playing can improve attention, working memory, and verbal memory. Some mental exercises were designed to train different aspects of cognition as can see in mental games such as crossword and sudoku. Chess playing is a game that requires a lot of aspects of cognition including complex planning, attention, and working memory. Mental exercises are not only in games. Some of them can be done along with everyday tasks such as doing normal activities with non-dominant hand, trying to use as multi sense as possible, experiencing unfamiliar environment, and having active lifestyle and active environment. Meditation, a self realization practice, trains selective attention. Chemically, it reduces stress, increases BDNF, and promotes neural plasticity.(29-31) Meditation is not limited the type that the performer sits with straight back eyes closed considering his breathe. This is known as mindfulness meditation. Meditation is also the basis of yoga, Qigong, and Tai chi. The idea of mental exercise goes along with cognitive-behavioral therapy (CBT) which new ideas are added or some ideas are avoided to alter ones perspective.
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Figure 11.1 Sleep architecture and neurophysiological characteristics of sleep stages. Sequential contributions of SWS and REM sleep to memory consolidation in a two-stage memory system.(32)
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In contrast to memory improvement, there are also some factors that can alter memory or produce memory errors.(33-37) The errors can be false memory or confabulation, the recollection of information that never occurred but was implanted by other people; misinformation, the misinterpretation of memory induced by affection of words; source confusion, the case that usually happen to childhood memory which the person cannot clearly remember how an event was experienced; imagination inflation, the false belief that something really occurred after repeated imagining of the event; DeeseRoediger-McDermott paradigm, a situation that a person recalls an false event or object after perceiving a set of related events; schematic error, an error belief that one has done a task because the task is a usual routine; and intrusion error, an error of putting unrelated subjects into one story because of the perception time difference of the two subjects approaches zero. Some scientists have tried to explain these mental errors. One of them is the spreading activation. It simplifies a memory as a node in a network. Once a memory event is activated, it may trigger the activation of other nodes because they are close in the network connection. When the association is stronger, they may be activated together can be presented as the error. The retrieval cues can increase the rate of the spreading of activation if the cues trigger the activation of nearby nodes. The errors can be considered temporally. If the previously learned information interferes the recall of newly learned information, it is called proactive interference. Retroactive interference, in opposite, is the inability to recall previous information because of the interference from new information. Errors sometimes are because of inappropriate encoding. Encoding with emotion strengthens memory, and encoding without or with less emotional impact can easily alter the information in the memory. Apart from interference, brain damage in the frontal lobe and medial temporal lobe can produce memory errors due to the implication to information management and judgement of these areas.
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Memory removal is another popular subject that is usually discussed about its ethical suitability. Humans not only want to have the best capability to remember, but they also want to choose the memory to be kept and erase the traumatic memory. This is a critical point for patients with posttraumatic stress disorder (PTSD).(38) It is the result of being in strong unpleasing event that triggers extreme emotional difficulty. Medicines like selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or beta blockers ( adrenergic receptor antagonists) such as propanolol are given to PTSD just for patients to be relieved from stress, anxiety, and depression. Drugs for memory clearance are still developing. The drug that has come to interest and may act directly on abolishing memory modulates protein kinase M this protein, (PKM ). Late phase LTP (L-LTP) which includes the . The inhibitor of maintenance of LTP is believed to be regulated by the activities of PKM
inhibitory peptide (ZIP), showed to abolish long-term memory in mice.(39-
41) Another promise may be on the other way by, not destroying the traumatic memory, but adding another memory to intervene the old memory. The hypothesis works on the process of reconsolidation as the old memory is labile or can be manipulated for a short period after being consciously recalled. The labile period is the critical time that memory may be altered by using CBT. However, the drugs or the techniques being developed have to be carefully considered whether they really erase memory or just inhibit memory from being recalled. New ideas in the manipulation of memory are growing their ways to become noninvasive and non-medicinal. It was previously started with CBT, but its mechanism of action and its efficiency are not stable in all patients. The emergence of the collaboration with engineering may propose some effective techniques for the study of memory. This will be the core concept for the next chapter.
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References
1. 2. 3. 4. Pohanka M. Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011;155(3):219-29. Rodda J, Carter J. Cholinesterase inhibitors and memantine for symptomatic treatment of dementia. BMJ. 2012;344:e2986. Tayeb HO, Yang HD, Price BH, Tarazi FI. Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors. Pharmacol Ther. 2012;134(1):8-25. Calabrese V, Cornelius C, Mancuso C, Lentile R, Stella AM, Butterfield DA. Redox homeostasis and cellular stress response in aging and neurodegeneration. Methods Mol Biol. 2010;610:285308. Yates FA. The Art of Memory: The University of Chicago Press; 1966 [cited 2012 23 July]. Available from: http://studyplace.ccnmtl.columbia.edu/w/images/9/9c/Yates-1966-Art-ofMemory-excerpt.pdf. Ebbinghaus H. Memory: A Contribution to Experimental Psychology1885 [cited 2012 23 July]: Available from: http://psychclassics.yorku.ca/Ebbinghaus/index.htm. Huesch MD, Sakakibara M. Forgetting the learning curve for a moment: how much performance is unrelated to own experience? Health Econ. 2009;18(7):855-62. Sikstrom S. Forgetting curves: implications for connectionist models. Cogn Psychol. 2002;45(1):95-152. Marcus Arenius CB, Gita Berntsson. An alternative interpretation of the von Restorff effect2007 [cited 2012 23 July]: Available from: http://www.ida.liu.se/~HKGBB5/rapporter-07/grupp2.pdf. Owen L, Sunram-Lea SI. Metabolic agents that enhance ATP can improve cognitive functioning: a review of the evidence for glucose, oxygen, pyruvate, creatine, and L-carnitine. Nutrients. 2011;3(8):735-55. PMCID: 3257700. McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet. 2012;379(9833):2291-9. Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM. Thiamine for Alzheimer's disease. Cochrane Database Syst Rev. 2001(2):CD001498. Morley JE, Banks WA. Lipids and cognition. J Alzheimers Dis. 2010;20(3):737-47. Karr JE, Alexander JE, Winningham RG. Omega-3 polyunsaturated fatty acids and cognition throughout the lifespan: a review. Nutr Neurosci. 2011;14(5):216-25.
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Schreurs BG. The effects of cholesterol on learning and memory. Neurosci Biobehav Rev. 2010;34(8):1366-79. PMCID: 2900496. Morris MC, Evans DA, Bienias JL, Scherr PA, Tangney CC, Hebert LE, et al. Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline. J Neurol Neurosurg Psychiatry. 2004;75(8):1093-9. PMCID: 1739176. Spencer JP, Vauzour D, Rendeiro C. Flavonoids and cognition: the molecular mechanisms underlying their behavioural effects. Arch Biochem Biophys. 2009;492(1-2):1-9. Williams RJ, Spencer JP. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med. 2012;52(1):35-45. Spencer JP. The impact of fruit flavonoids on memory and cognition. Br J Nutr. 2010;104 Suppl 3:S40-7. Sarter M, Parikh V. Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci. 2005;6(1):48-56. Meck WH, Williams CL. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci Biobehav Rev. 2003;27(4):385-99. Higgins JP, Flicker L. Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev. 2003(3):CD001015. Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret P, Jaffard R. Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behav Brain Res. 2003;145(1-2):37-49. Goodman AB. Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. J Cell Physiol. 2006;209(3):598-603. Kawade R. Zinc status and its association with the health of adolescents: a review of studies in India. Glob Health Action. 2012;5:7353. PMCID: 3328203. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003(4):CD004514. Bekinschtein P, Oomen CA, Saksida LM, Bussey TJ. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin Cell Dev Biol. 2011;22(5):536-42. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86(9):876-84. PMCID: 3258000.
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Biegler KA, Chaoul MA, Cohen L. Cancer, cognitive impairment, and meditation. Acta Oncol. 2009;48(1):18-26. Lutz A, Slagter HA, Dunne JD, Davidson RJ. Attention regulation and monitoring in meditation. Trends Cogn Sci. 2008;12(4):163-9. PMCID: 2693206. Keng SL, Smoski MJ, Robins CJ. Effects of mindfulness on psychological health: a review of empirical studies. Clin Psychol Rev. 2011;31(6):1041-56. Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11(2):114-26. Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH. Toward a neurobiology of delusions. Prog Neurobiol. 2010;92(3):345-69. Schacter DL, Guerin SA, St Jacques PL. Memory distortion: an adaptive perspective. Trends Cogn Sci. 2011;15(10):467-74. PMCID: 3183109. Schacter DL, Slotnick SD. The cognitive neuroscience of memory distortion. Neuron. 2004;44(1):149-60. Kavanau JL. Memory failures, dream illusions and mental malfunction. Neuropsychobiology. 2001;44(4):199-211. Cox RE, Barnier AJ. Hypnotic illusions and clinical delusions: hypnosis as a research method. Cogn Neuropsychiatry. 2010;15(1):202-32. Bisson J, Andrew M. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2007(3):CD003388. Kwapis JL, Jarome TJ, Gilmartin MR, Helmstetter FJ. Intra-amygdala infusion of the protein kinase Mzeta inhibitor ZIP disrupts foreground context fear memory. Neurobiol Learn Mem. 2012. Li YQ, Xue YX, He YY, Li FQ, Xue LF, Xu CM, et al. Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory. J Neurosci. 2011;31(14):5436-46. PMCID: 3150199. von Kraus LM, Sacktor TC, Francis JT. Erasing sensorimotor memories via PKMzeta inhibition. PLoS One. 2010;5(6):e11125. PMCID: 2886075.
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Models and Algorithms
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Chapter 12 Models and Algorithms for the Study of Memory and Cognitive Neural Prosthesis
Akara Metasuk A human brain can have 80-120 billon neuronal cells. Each cell can have 1,00010,000 synapses with other cells. This means that the connections in a brain can be as much as 1,000,000,000,000,000 connections. Since the brain is complex, the study of the functions of the brain becomes difficult to interpret. In biology, scientists usually introduce or block some chemicals or remove some structure of the brain to observe the changes that may happen. The data draws some connections for biologists to interpret the functions of particular chemicals or brain structures. This is a very tough issue because single chemical or single brain area can produce effects on many aspects. The idea of Reductionism simplifies the complex structure of the brain to a reduced form that can be easily understood. The functions of the brain are also simplified in mathematic algorithms. More applications from the understanding of the brain later result in the development of braincomputer interface and neuroprosthetics. Memory deals with the latter one as in cognitive neural prosthetics. Here are some animal models that have been widely used for the studies in Neuroscience: (Table 12.1)
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Table 12.1 Animal models in neuroscience Number of neurons in cerebral cortex
Animal models
Studies
Number of synapses
Life expectancy
Caenorhabditis elegans (Roundworms) Aplysia californica (Sea slugs) Drosophila melanogaster (Fruit flies) Danio rerio (Zebrafish) Taeniopygia guttata (Zebra finch) Mus musculus (Mice) Rattus norvegicus (Rats)
4,000,000
Neuronal connectivity
302
4000
2-3 weeks
Synaptic plasticity
18,000 20,000
1 year
Depression, olfactory learning
100,000
10,000,000
26 - 33 days
Neurodevelopment
3.5 years
Vocalization/Language
5-7 years
Neurodegeneration, All declarative and nondeclarative learning

15,000,000 21,000,000
100,000,000,000
4 years
448,000,000,000
3.8 years
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10 30 Cats Dogs Sheeps Macaca mulattaa (Rhesus macaques) Pan troglodytes (Chimpanzees) Complex behavior, Brain-computer interface
5,500,000,00 6,200,000,000 ?
Vision, Complex learning
years
300,000,000 1,000,000,000,000 160,000,000 10,000,000,000,000
[Depends on the strains]
480,000,000
40 years
55 60 years
Abstract memory processing models that focus on the bigger picture of memory including Atkinson-Shiffrein multi-store memory model and Baddeleys working memory model are briefly explained in chapter 2 of this essay. Representational theory of mind assumes that the external environment is perceived and can be expressed or represented in the internal system by sets of symbols due to algorithms.(1) Some representations are argued that they are not actually represented. Such kinds are mental representations; for example, pain and emotions. They are considered to be non representational and are called qualia in computational theory of mind.(2-3) Computational theory of mind envisions the brain working like a functioning computer. (Figure 12.1) It stores algorithms that manage step-by-step how the output looks like. This is not to confuse with the computer metaphor idea that states that the brain is a computer. The computational theory only gives the idea that the brain is a symbol manipulator that works
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like a computer or a Turing machine except the fact that the brain may function a bit more complex. The idea that determines behaviors and mental outputs as the results of interconnected networks is known as connectionism.
Figure 12.1 Supervised network with backpropagation learning rule.(4) New models have been developed to further determine the function of the brain after connectionism. A lot of them put their roots on memory-prediction framework theory proposed by Jeff Hawkins.(5) The theory is used to predict simple outputs from the activities brain areas including cortex, hippocampus, and thalamus. The concept is that the inputs are hierarchically gathered from bottom-up, and the outputs are processed from top-down and are predicted by the guidance from the lower rank hierarchy. The lower hierarchy is less organized and has a lot of possibility to continue on. When going up the rank, the signals are compared to the past information, or the expectation. The expectations can modulate the outputs differently because the expectations change with the external experience. If there are some parts of new information that do not match with the expectation, new connections are created. This idea is consistent to biological learning. More details about
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this theory can be found in the book On Intelligence written by Hawkins. The ability to learn is also a big inspiration to the design of intelligent machines. Bottom-up strategy of robot design allows simple algorithms for the robots to learn and complete all the programs by itself. In contrast, top-down strategy tries to put all programs into the robot. However, the top-down strategy is not yet, and maybe never be, successful. Cog, a bottom-up robot, learns and improves its program just like how biological brain does.(6) (Figure 12.2)
Figure 12.2 Static extremes of Kismet's facial expressions. During operation, the 11 degrees of-freedom for the ears, eyebrows, mouth, and eyelids vary continuously with the current emotional state of the robot.(6)
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Biological neural network is usually too complex for brain algorithms to be identified. Artificial neural networks (ANN) are designed to mimic the properties of neurons and perform functions just like biological neural network by using artificial units, nodes or neurodes, being connected to one another.(4, 7-8) The algorithms are basically defined as: y = f(x) or f: X Y Equation 12.1 where x X is the input and y Y is the output. The algorithms may vary throughout the network such as starting from H = h(X) then G = g(H) and F = f(G). (Figure 12.3) Learning is the process after the system looked for the optimal f (the f*) that requires smallest cost or C(f*) in the cost function C as denoted by: C(f*) C(f) f F Equation 12.2 The common cost is the mean-squared error between the output f*(x) and the expected value f(x). This is called the supervised learning since the data have to be compared or supervised by the past data. In addition, each artificial neuron generate its output (y) that follows the transfer function ( ) which the synaptic signal (x) and the synaptic weight (w) between the pre-synaptic neuron (i) and post-synaptic neuron (j) have to be considered. An artificial neuron can be simplified as: Yj = Equation 12.3 where m+1 is the number of inputs. The determination of synaptic weight and the transfer function are described by other models such as the model by Hodgkin-Huxley, FitzHugeNagumo, Morris-Lecar, and Hindmarsh-Rose. ( j = 0 wijxi)
m
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Figure 12.3 Tree-shaped hierarchy. Each subregion in level 0 receives image fragment of size 4x4 pixels. Each subregion in level 1 receives input from 4 children in level 0. A single subregion in level 2 receives input from all level 1 subregions.(5) Brain-computer interface (BCI) has been developed on the principles of algorithms that are designed to extract biological information or to stimulate biological actions. Most of the applications aim to promote sensorimotor complements such those can be applied for people who are defected in some organs. On the other hand, cognitive neural prosthesis aims to restore, or even augment, cognitive functions. It started from the development of algorithms that mimic the biological algorithm in a limited area, for example in the hippocampal CA3 to CA1 network.(9) Most of the successful studies in hippocampal prosthesis were carried out by Theodore Berger.(10) (Figure 12.4) The techniques are developed along with neurochips and multi-electrode arrays. He worked on the issue by characterizing accurate input/output (I/O) or multi-input/multi-output (MIMO) parameters mathematically, not by trying to crack the actual algorithms of the biological neural network. Recent study with Samuel Deadwyler showed that the extracted parameter can perfectly mimic the connection of CA3 to CA1. Interestingly, the stimulation of CA1 with specific patterns can improve memory of mice in a delayed-nonmatch-to-sample (DNMS) task, and
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the infusion of hippocampus with glutamatergic blocer MK801 can be recovered by the electrical stimulation.
Figure 12.4 MIMO model repair of hippocampal encoding with previously effective CA1 stimulation patterns delivered at the time of the SR.(10) The study of biological memory is not limited to only the field of biology. Researchers worldwide are working together to find the master key of memory. Finally, the integration of mathematics and engineering with biology may support the advance in neuroscience.
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References
1. 2. 3. 4. 5. Sterelny K. The Representational Theory of Mind: Basil Blackwell; 1990. Available from: http://mugwump.pitzer.edu/~bkeeley/CLASS/FoNS/Sterelny.pdf. Gerad Casey AM. The Computational Metaphor and Cognitive Psychology. The Irish Journal of Psychology. 1989;10(2):143-61. Cisek P. BEYOND THE COMPUTER METAPHOR: BEHAVIOR AS INTERACTION. Journal of Consciousness Studies. 1999;6:125-42. Agatonovic-Kustrin S, Beresford R. Basic concepts of artificial neural network (ANN) modeling and its application in pharmaceutical research. J Pharm Biomed Anal. 2000;22(5):717-27. Garalevicius SJ. MemoryPrediction Framework for Pattern Recognition: Performance and Suitability of the Bayesian Model of Visual Cortex. American Association for Artificial Intelligence. 2007. Rodney A. Brooks CB, Matthew Maranovic, Brian Scassellati, Matthew M. Williamson. The Cog Project: Building a Humanoid Robot. Springer-Verlag. 1998;1562. Dreiseitl S, Ohno-Machado L. Logistic regression and artificial neural network classification models: a methodology review. J Biomed Inform. 2002;35(5-6):352-9. Thuijsman F. Artificial Neural Networks: An Introduction To Ann Theory And Practice: Springer; 1991. Available from: http://books.google.co.th/books?id=03DfRqUrTwsC&lpg=PA1&ots=frQr4pSKBm&dq=artificial% 20neural%20network%20book&lr&pg=PA1#v=onepage&q=artificial%20neural%20network%20b ook&f=false. Zoran Nenadic DSR, Richard A. Anderson, Joel W. Burdick. Advances in Cognitive Neural Prosthesis: Recognition of Neural Data with an Information-Theoretic Objective. CiteSeerX. 2008. Berger TW, Hampson RE, Song D, Goonawardena A, Marmarelis VZ, Deadwyler SA. A cortical neural prosthesis for restoring and enhancing memory. J Neural Eng. 2011;8(4):046017. PMCID: 3141091.
6. 7. 8.
9. 10.
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Pa ge |A
Forthcoming Studies
Akara Metasuk The study about memory has long been propagated in neuroscience. What we know today about memory is all about what happens when memory processes are performed and what the factors that have effects to memory are. There is still no evidence that can exactly answer what memory is. Connectionism strategy that draws the similarities of the brain and the computer may grow a way to get the answer. Computer memory is stored as a set of binary forms of 0 and 1, or off and on state of the connection. Different memory is stored by different sets of connections. The concept may be similar to biological memory in some aspects when the brain is considered to be a lump of neuronal connections. Some studies showed that different information of perception and imagery can trigger different specific areas of the brain. The studies have been reduced to the study in different neuronal cell groups and the differences in activation pattern are still found with different stimuli. The study about the patterns of neuronal connection after the perception of different stimuli may help answer how memory is stored in a non-abstract way in the brain. Another question is about how the brain records information. Some studies showed that the brain activates similar patterns during perception and during imagination. Synaptogenesis is known to be the core process of neuronal plasticity related to the formation of memory. However, it is unsafe to deduce that this process is required for the formation of new information. Possibly, it might be just a process that strengthens the recall of the information. To answer the question, the interaction of synaptogenesis to perception and imagination may have to be studied.
Akara Metasuk
Pa ge |B
Acknowledgement
Akara Metasuk This qualifying examination is managed by the staffs at The Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University. I am grateful to Assoc.Prof. Banthit Chetsawang, Prof. Piyarat Govitrapong, Assoc.Prof. Wipawan Thangnipon, Asst.Prof. Nuanchan Chatubhakdikul, Dr. Narawut Pakaprot and all lectures and academic staffs for his/her advices and discussions during the examination. I also thank my friends for inspiring me by introducing and sharing papers before the examination. Many of those papers have become the valuable resources for this writing. The initial theoretical study and the academic fee were funded by The Royal Golden Jubilee Ph.D. Program.
Akara Metasuk

Biological Memory

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Biological Memory

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What We Know and Where We Are Going

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Introduction to Biological Memory

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

History of the Study of Memory

Chapter 1 History of the Study of Memory

History of the Study of Memory

History of the Study of Memory

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

History of the Study of Memory

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

History of the Study of Memory

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

History of the Study of Memory

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

History of the Study of Memory

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Chapter 2 Classification of Memory and the Processing

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand

Classification of Memory and the Processing

Qualifying Exam in Neurosciences

RCN, Mahidol University, Thailand