ANATOMY AND PHYSIO

The central nervous system (CNS) is the part of the nervous syst
em that integrates the information that it receives from, and coordinates the ac
tivity of, all parts of the bodies of bilaterian animals that is, all multicellula
r animals except sponges and radially symmetric animals such as jellyfish. It co
ntains the majority of the nervous system and consists of the brain and the spin
al cord. Some classifications also include the retina and the cranial nerves in
the CNS. Together with the peripheral nervous system, it has a fundamental role
in the control of behavior. The CNS is contained within the dorsal cavity, with
the brain in the cranial cavity and the spinal cord in the spinal cavity. In ver
tebrates, the brain is protected by the skull, while the spinal cord is protecte
d by the vertebrae, and both are enclosed in the meninges.
development:
During early development of the vertebrate embryo, a longitudina
l groove on the neural plate gradually deepens as ridges on either side of the g
roove (the neural folds) become elevated, and ultimately meet, transforming the
groove into a closed tube, the ectodermal wall of which forms the rudiment of th
e nervous system. This tube initially differentiates into three vesicles (pocket
s): the prosencephalon at the front, the mesencephalon, and, between the mesence
phalon and the spinal cord, the rhombencephalon. (By six weeks in the human embr
yo) the prosencephalon then divides further into the telencephalon and diencepha
lon; and the rhombencephalon divides into the metencephalon and myelencephalon.
As the vertebrate grows, these vesicles differentiate further st
ill. The telencephalon differentiates into, among other things, the striatum, th
e hippocampus and the neocortex, and its cavity becomes the first and second ven
tricles. Diencephalon elaborations include the subthalamus, hypothalamus, thalam
us and epithalamus, and its cavity forms the third ventricle. The tectum, pretec
tum, cerebral peduncle and other structures develop out of the mesencephalon, an
d its cavity grows into the mesencephalic duct (cerebral aqueduct). The metencep
halon becomes, among other things, the pons and the cerebellum, the myelencephal
on forms the medulla oblongata, and their cavities develop into the fourth ventr
icle.
HYPOTHALAMUS:
Anatomy
The hypothalamus is an integral part of the substance of the bra
in. A small cone-shaped structure, it projects downward, ending in the pituitary
(infundibular) stalk, a tubular connection to the pituitary gland. The round bo
ny cavity containing the pituitary gland is called the sella turcica. The poster
ior portion of the hypothalamus, called the median eminence, contains many neuro
secretory cells. Important adjacent structures include the mammillary bodies, th
e third ventricle, and the optic chiasm, the last being of particular concern to
physicians because pressure from expanding tumours or inflammations in the hypo
thalamus or pituitary gland may result in severe visual defects or total blindne
ss. Above the hypothalamus is the thalamus. (For discussion of the function of t
hese surrounding structures, see the nervous system.)
physiology:
Regulation of hormone secretion
The hypothalamus regulates homeostasis. It has regulatory areas
for thirst, hunger, body temperature, water balance, and blood pressure, and lin
ks the nervous system to the endocrine system.
 The hypothalamus, like the rest of the brain, consists of interc
onnecting nerve cells ( neurons) with a rich blood supply. To understand hypotha
lamic function it is necessary to define the various forms of neurosecretion. Fi
rst, there is neurotransmission, which occurs throughout the brain and is the pr
ocess by which one nerve cell communicates with another at an intimate interming
ling of projections from the two cells (a synapse). This transmission of an elec
trical impulse from one cell to another requires the secretion of a chemical sub
stance from a long projection from one nerve cell body (the axon) into the synap
tic space. The chemical substance that is secreted is called a neurotransmitter.
Neurologists have long been aware of four classical neurotransmi
tters: epinephrine, norepinephrine, serotonin, and acetylcholine, but recently t
here have emerged a large number of additional neurotransmitters, of which an im
portant group is the neuropeptides. While bioamines and neuropeptides function a
s neurotransmitters, some of them also perform the role of neuromodulators; they
do not act directly as neurotransmitters but rather as inhibitors or stimulator
s of neurotransmission. Well-known examples are the opioids (for example, enkeph
alins), so named because they are the naturally occurring peptides with a strong
affinity to the receptors that bind opiate drugs such as morphine and heroin. I
n effect, they are the body's opiates.
Thus the brain, and indeed the entire central nervous system, co
nsists of an extraordinary network of neurons interconnected by neurotransmitter
s. The secretion of specific neurotransmitters, modified by neuromodulators, len
ds an organized, directed function to the overall system. These neural connectio
ns extend upward from the hypothalamus into other key areas, including the cereb
ral cortex. The result is that intellectual and functional activities as well as
external influences, including stresses, can be funneled into the hypothalamus
and thence to the endocrine system, from which they may exert effects on the bod
y.
In addition to secreting neurotransmitters and neuromodulators,
the hypothalamus synthesizes and secretes a number of neurohormones. The neurons
secreting neurohormones are true endocrine (neurohemal) cells in the classical
sense since secretory granules containing neurohormones travel from the cell bod
y through the axon to be extruded, where they enter directly a capillary network
, thence to be transported through the hypophyseal-portal circulation to the ant
erior pituitary gland.
Finally, the neurohypophysis, or posterior lobe of the pituitary
gland, provides the classical example of neurohormonal activity. The secretory
products, mainly vasopressin and oxytocin, are extruded into a capillary network
, which feeds directly into the general circulation.
The existence of hormones of the hypothalamus was predicted well
before they were detected and chemically characterized, and they have been stud
ied intensively by many investigators. Two groups of American investigators, led
by Andrew Schally and Roger Guillemin, respectively, shared the Nobel Prize for
Physiology or Medicine for 1977 for their research on pituitary hormones.
These neurohormones are known as releasing hormones because the
major function generally is to stimulate the secretion of hormones originating i
n the anterior pituitary gland. They consist of simple peptides (chains of amino
acids) ranging in size from only three amino acids (thyrotropin-releasing hormo
ne) to 44 amino acids (growth hormone-releasing hormone).

hormones:
Thyrotropin-releasing hormone
 Thyrotropin-releasing hormone (TRH), a neurohormone, is
the simplest of the hypothalamic neuropeptides. It consists essentially of three
amino acids in the sequence glutamic acid histidine proline. The simplicity of this
structure is deceiving for TRH is involved in an extraordinary array of functio
ns. Not only is it a neurohormone that stimulates the secretion of thyroid-stimu
lating hormone from the pituitary, and, quite independently, the secretion of an
other pituitary hormone called prolactin, but it also subserves other central ne
rvous system activities because it is a widespread neurotransmitter or neuromodu
lator within the brain and spinal cord. There is evidence that TRH is involved i
n the control of body temperature and that it has psychological and behavioral e
ffects, at least in animals. It may also have therapeutic value. There are studi
es suggesting that it mitigates the damage induced by spinal cord injury and tha
t it leads to some improvement in the nervous disease known as amyotrophic later
a l sclerosis (Lou Gehrig's disease).
These multiple effects are less surprising when it is co
nsidered that TRH appeared very early in the evolutionary scale of vertebrates a
nd that, while the concentration of TRH is greatest in the hypothalamus, the tot
al amount of TRH in the remainder of the brain far exceeds that of the hypothala
mus. The TRH-secreting cells are subject to stimulatory and inhibitory influence
s from higher centres in the brain and they also are inhibited by circulating th
yroid hormone. In this way TRH forms the topmost segment of the hypothalamic-pit
uitary-thyroid axis.

Gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH), a neurohormone al
so known as luteinizing hormone-releasing hormone (LHRH), is a peptide chain of
10 amino acids. It stimulates the synthesis and release of the two pituitary gon
adotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Whi
le some investigators hold that there are two types of GnRH, most evidence suppo
rts the conclusion that only one type of neuropeptide stimulates the release of
the two gonadotropins and that the variations in levels of both gonadotropins in
the circulation are due to other modulating factors.
Characteristic of all releasing hormones and most striki
ng in the case of GnRH is the phenomenon of pulsatile secretion. In normal indiv
iduals, GnRH is released in spurts at intervals of about 80 minutes. The pulsati
le administration of GnRH in large doses results in an ever-increasing concentra
tion of gonadotropins in the blood. In striking contrast, the constant infusion
of GnRH suppresses gonadotropin secretion. This phenomenon is advantageous for p
ersons for whom suppression is important. Such persons include children with pre
cocious puberty, and elderly men with cancer of the prostate. On the other hand,
pulsatile administration of GnRH is efficacious in men or women in whom deficie
ncy of gonadal function is due to impaired secretion of GnRH. A potential applic
ation of this phenomenon is the synthetic modifications of GnRH as a male as wel
l as a female contraceptive.
Neurons that secrete GnRH have connections to an area of
the brain known as the limbic system, which is heavily involved in the control
of emotions and sexual activity. Studies in rats deprived of pituitary glands an
d ovaries but maintained on physiological amounts of female hormone (estrogen) h
ave demonstrated that the injection of GnRH results in complex and striking chan
ges in posture characteristic of the receptive female stance for sexual intercou
rse.
Some individuals have hypogonadism (in which the functio
nal activity of the gonads is decreased and sexual development is inhibited) due
to a congenital deficiency of GnRH, which responds to treatment with GnRH. Most
 of these people also suffer from hypothalamic disease and are deficient in othe
r releasing hormones as well, but there are also individuals in whom GnRH defici
ency is isolated and associated with a loss of the sense of smell (anosmia). Abn
ormalities in the pulses of GnRH secretion result in subnormal fertility, abnorm
al or absent menstruation, and possibly cystic disease of the ovary or even ovar
ian cancer
Corticotropin-releasing hormone
Corticotropin-releasing hormone (CRH), a neurohormone, i
s a large peptide consisting of a single chain of 41 amino acids. It stimulates
not only secretion of corticotropin in the pituitary gland but also the synthesi
s of corticotropin in the corticotropin-producing cells (corticotrophs) of the a
nterior lobe of the pituitary gland. Many factors, both neurogenic and hormonal,
regulate the secretion of CRH, since CRH is the final common element directing
the body's response to all forms of stress, whether physical or emotional, exter
nal or internal. (This key role of CRH in the hypothalamic-pituitary-adrenal axi
s is discussed below in connection with the adrenal gland.) Among the hormones t
hat play an important role in modulating the influence of CRH is cortisol, the m
ajor hormone secreted by the adrenal cortex, which, as part of the negative feed
back servomechanism (exerting control over another system through negative feedb
ack), blocks the secretion of CRH. Vasopressin, the major regulator of the body'
s exc retion of water, has an additional ancillary role in sti
mulating the secretion of CRH.
Excessive secretion of CRH leads to an increase in the s
ize and number of corticotrophs in the pituitary gland, often resulting in a pit
uitary tumour. This, in turn, leads to excessive stimulation of the adrenal cort
ex, resulting in high circulating levels of adrenocortical hormones, the clinica
l manifestations of which are known as Cushing's syndrome. Conversely, a deficie
ncy of CRH-producing cells can, by a lack of stimulation of the pituitary and ad
renal cortical cells, result in adrenocortical deficiency. (These conditions are
discussed below.
Growth hormone-releasing hormone
Like CRH, growth hormone-releasing hormone (GHRH) is a l
arge peptide. A number of forms have been described that differ from one another
only in minor detail and in the number of amino acids (varying from 37 to 44).
Unlike the other neurohormones, GHRH is not widely distributed in other parts of
the brain. It is stimulated by stresses, including physical exercise, and secre
tion is blocked by a powerful inhibitor called somatostatin (see below Somatosta
tin). Negative feedback control of GHRH secretion is mediated largely through co
mpounds called somatomedins, growth-promoting hormones that are generated when t
issues are exposed to growth hormone itself.
An excess of circulating growth hormone in adults leads
to a condition called acromegaly. Rarely, a benign tumour, called a hamartoma, l
ocated in the hypothalamus may produce excessive amounts of GHRH, leading to acr
omegaly. Equally rare are tumours arising in the islets of Langerhans of the pan
creas that may secrete excessive quantities of GHRH. Indeed, GHRH was first succ
essfully isolated and analyzed from such an ectopic (abnormally positioned) horm
one-producing tumour. Isolated deficiency of GHRH (in which there is normal func
tioning of the hypothalamus except for this deficiency) may be the cause of one
form of dwarfism, a general term applied to all individuals with abnormally smal
l stature.
Somatostatin
Somatostatin refers to a number of polypeptides consisti
ng of chains of 14 to 28 amino acids. The name was coined when its discoverers f
ound that an extract of the hypothalamus strongly inhibited the release of growt
h hormone from the pituitary gland. Somatostatin is also a powerful inhibitor of
pituitary TSH secretion. Somatostatin, like TRH, is widely distributed in the c
entral nervous system and in other tissues. It serves an important paracrine fun
ction in the islets of Langerhans, by blocking the secretion of both insulin and
glucagon from adjacent cells. Somatostatin has emerged not only as a powerful b
locker of the secretion of GH, insulin, glucagon, and other hormones but also as
a potent inhibitor of many functions of the gastrointestinal tract, including t
he secretion of stomach acid, the secretion of pancreatic enzymes, and the proce
ss of intestinal absorption. Despite these multiple, widespread actions, the ter
m somatostatin has persisted because of its major role as a regulator of GH secr
etion , and impaired somatostatin secretion may cause some for
ms of hypersecretion of growth hormone.
No examples of somatostatin deficiency have been found,
but a tumour called a somatostatinoma has been well characterized in a number of
patients. Persons with a somatostatinoma have cramping abdominal pain, persiste
nt diarrhea, a mild elevation of blood glucose levels, and sudden flushing of th
e skin.
Prolactin-inhibiting and releasing hormones
The hypothalamic regulation of prolactin secretion from
the pituitary is different from the hypothalamic regulation of other pituitary h
ormones in two respects. First, the hypothalamus primarily inhibits rather than
stimulates the release of prolactin from the pituitary (the hypothalamus stimula
tes the release of all other pituitary hormones). Thus, if pituitary cells are r
emoved from the influence of the hypothalamus, few or none of the pituitary horm
ones are secreted, except for prolactin, which continues to be secreted by the p
rolactin-secreting cells (lactotrophs). Second, this major inhibiting factor is
not a neuropeptide, but rather the neurotransmitter dopamine, a fact exploited i
n afflicted persons by physicians who are able to reduce abnormally high concent
rations of prolactin by using drugs that mimic the prolactin-inhibiting effects
of dopamine. Another prolactin-inhibiting factor (PRF) comes into play primarily
during pregnancy and lactation. Prolactin-stimulating factors also exist, among
them TRH.
Prolactin deficiency is known to occur, but only rarely.
Excessive prolactin production (hyperprolactinemia) is a common endocrine abnor
mality, and the prolactinoma is the most frequently encountered pituitary tumour
.
Gastrointestinal neuropeptides
Although modern endocrinology began with the discovery t
hat a substance, secretin, secreted into the blood from the cells lining the gas
trointestinal tract stimulates the secretion of pancreatic juices, little attent
ion was subsequently paid to gastrointestinal hormones. When investigators began
to examine the distribution of neuropeptides within the body, however, there em
erged a bewildering variety of these hormones, not only within the brain but als
o in the lining of the gastrointestinal tract and in other organs. The list incl
udes glucagon, the enkephalins, secretin, cholecystokinin, gastrin, calcitonin,
angiotensin, substance P, pancreatic polypeptide, neuropeptide Y (a human varian
t of a peptide called bombesin), delta-sleep-inducing peptide, and vasoactive in
testinal peptide. The actions and interactions of these hormones both in the int
estinal tract and in the brain are complex and are the subject of continuing inv
estigations. Briefly, these peptides play important roles in the transmission an
d inh ibition of pain stimuli, in eating and drinking behaviou
r, in memory and learning, in the regulation of body temperature, in the inducti
on of sleep, and in sexual behaviour.