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CONTENTS

Sleep Phylogeny: Clues to the Evolution and Function of Sleep

Jerome M. Siegel

Introduction............................................................................................................163 Terrestrial Mammals..............................................................................................164 Aquatic Mammals..................................................................................................168 Reptiles ..................................................................................................................171 Conclusions............................................................................................................174 References..............................................................................................................174

INTRODUCTION
A persuasive argument for the importance of sleep rests on its ubiquity among animals. All mammals sleep.1 Reptiles appear to sleep, although by some measures they may not.29 It has not been conclusively demonstrated that sh sleep, although some species show marked circadian rhythms of activity.10,11 To meet the accepted denition of sleep, animals must show periods of inactivity with raised arousal thresholds and must show sleep debt when deprived, leading to rebound sleep when deprivation is ended. Fruit ies (Drosophila melanogaster) show periods of inactivity with raised arousal thresholds and sleep rebound after deprivation.1214 If such periods are homologous to sleep in vertebrates, one must consider any reported absence of sleep in higher vertebrates as an error due to inadequate assessment or to be an evolved adaptation to particular ecological niches that has done away with a sleep state present in ancestral animals. This chapter discusses the special situation of marine mammals, which appear to have evolved adaptations that at the very least mask some aspects of sleep and certainly dispense with the need for immobility during what otherwise appears to be sleep. A further issue is the nature of sleep. Most mammals1,15 and birds16 show evidence of REM sleep also known as paradoxical sleep (PS) although this state may not exist in certain marine mammals.17 Amounts of sleep differ substantially between species, with some sleeping as little as 2 h per day and others as much as 20 h.1,15 Surely these enormous variations

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offer some insight into the physiological needs responsible for sleep. Although animals in different ecological niches might most adaptively have evolved differing durations of activity and inactivity, it is unlikely that no animals would have evolved a complete or nearly complete absence of sleep unless it served some vital function. The cost of sleep in terms of vulnerability, loss of time to eat, procreate, and gain an edge in competition with other animals is considerable. Certainly contemporary humans make major efforts to reduce sleep time to achieve their goals. Differences in sleep amounts seem to be systematically related to certain constitutional variables, suggesting that underlying physiological factors, rather than ecological niche, determine sleep need. The study of sleep phylogeny can help explain the essence of sleep debt; i.e., which physiological, neurochemical, and genetic events are conserved across sleep in differing animals.

TERRESTRIAL MAMMALS
Although there are approximately 4,000 mammalian species, fewer than 100 have been studied under laboratory conditions. Most of these have been observed in only a single study. Perhaps an additional 100 have been observed in zoos. Certainly there is no need to study sleep in all mammalian species; however it is likely that a thorough examination of sleep physiology, exploring the genetic variations and adaptations that have occurred over more than 100,000,000 years of mammalian evolution, may reveal aspects of sleep not seen in the four or ve laboratory species that have been most thoroughly studied. For example, humans and rats have been shown to have a clear link between REM sleep and penile erections.16,19 A recent study of sleep in the armadillo revealed that penile erections occur in non-REM sleep, but not in REM sleep in this species.20 Such observations are not merely a curiosity but speak to the issue of which aspects of sleep are core phenomena and which are perhaps epiphenomena not linked to particular sleep-waking states. In this case, the ndings suggest that certain aspects of sympathetic and parasympathetic control during sleep differ across species. One may speculate that other aspects of standard sleep signs in rats, cats, and humans, such as high voltage electroencephalogram (EEG) during nonREM sleep, low voltage EEG during REM sleep or high voltage EEG occurring simultaneously in both hemispheres, may not be essential for sleep. Many of the largest mammals such as elephants, and giraffes have only been studied by visual observation. Understanding sleep in these animals is crucial, because the extreme points in any cross species comparison can be most informative as to the underlying variables that determine sleep amounts and physiology. Perhaps the most surprising conclusion from studies of mammalian sleep is that knowing the order to which an animal belongs tells you very little about the amount of total sleep or REM sleep they have.1,15 In other words, as a group rodents do not have characteristic sleep patterns that differentiate them from carnivores, primates, artiodactyls, insectivores, and so on. Each of these groups shows a wide and overlapping range of total and REM sleep amounts. Each order is characterized by a common genetic inheritance that produces characteristic behaviors, brain and body anatomy, intelligence, diet, and reproductive physiology that tends to differentiate it from other orders. Yet their sleep is not characteristic of the group, suggesting that

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TABLE 9.1 Correlations between Sleep Parameters and Constitutional Variables

Total Daily Sleep Time Body weight Brain weight Metabolic rate Encephalization quotient
a b

Quiet Sleep Time 0.53a 0.48a 0.30b 0.10

REM Sleep Time 0.45a 0.52a 0.13 0.20b

REM Sleep% 0.12 0.25 0.09 0.30b

Sleep Cycle Length 0.83a 0.89a 0.82 0.52b

0.53a 0.55a 0.33b 0.17

P<0.001. P0.05.

these variables do not determine sleep amount. A comprehensive analysis of the determinants of sleep time looking at body weight, metabolic rate, brain weight, encephalization quotient (brain-to-body weight ratio), body temperature, neonatal brain weight as a percentage of adult weight, gestation period, and litter size concluded that total sleep time was most closely correlated with body weight15 (Table 9.1). This was a negative correlation; i.e., big animals sleep less. Body weight is inversely related to metabolic rate, so we can say that animals with higher metabolic rate have more total sleep time. The implications of this is discussed in the Conclusions section. Among terrestrial mammals REM sleep amounts are positively correlated with total sleep amounts; however this explains only a small amount of the total variance in REM sleep time. It has been noted that predator animals and animals with safe sleeping sites have relatively larger amounts of REM sleep.21 This makes some sense, because arousal thresholds are elevated in some animals in REM sleep, so it might be dangerous for prey animals to have large amounts of REM sleep., It is not true, however, that REM sleep is deep sleep in all animals.22 In humans, for example, arousal from REM sleep is more rapid than from non-REM sleep, and there is evidence that in general animals aroused from REM sleep function better than those aroused from non-REM sleep.23 It is difcult to quantify safety of sleep site by measures such as frequency of death during sleep. Sites that seem exposed may in fact be safe, and there is little evidence that animals are disproportionately hunted during sleep. Therefore, while there is little doubt that certain predator animals have large amounts of REM sleep, this relation does not appear to adequately explain REM sleep time. An alternate correlate of REM sleep time is how immature animals are at birth. At birth all mammals so far examined have their maximal amounts of REM sleep. Amounts diminish with age to adult levels.24 Animals such as rats or cats that are born relatively immature have a greater elevation in REM sleep at birth. Animals such as horses or guinea pigs that are born relatively mature have little elevation of REM sleep at birth. This suggests that REM sleep may have some role in brain or body development or in the protection of small animals without substantial thermoregulatory capacity from hypo- or hyperthermia. This role has not been identied. Furthermore, even though animals that are immature at birth have

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TABLE 9.2 Correlations of REM Sleep Parameters with Measures of Neonatal Maturity and Reproductive Variables
REM Sleep Time Altricial-precocial rating Neonatal brain weight (% adult) Litter size
a b

REM Sleep% of Total Sleep Time 0.45b 0.55b 0.41b

0.66a 0.61a 0.51a

P<0.001. P0.05.

decreasing REM sleep amounts as they age, they continue to have higher REM sleep amounts when they reach adulthood (Table 9.224). No theory has been offered as to why this is; however, from a statistical standpoint, the correlation between immaturity at birth and REM sleep time in adulthood accounts for a large amount of the interspecies variability in REM sleep time between mammals. Figure 9.125 shows some mammals with relatively high and low amounts of REM sleep. It is important to note that humans do not have unusual amounts of REM sleep either in terms of the number of hours per day or the percent of sleep time devoted to REM sleep (Figure 9.1); rather the amount of REM sleep time shown by humans is in line with our intermediate state of maturity at birth. This is obviously a problem for any theory hypothesizing that REM sleep amount is linked to intellectual capacity or any other characteristic in which humans are believed to be at an extreme within the animal kingdom.25 The monotremes are one of the three branches of the mammalian line, the other two being the placentals and the marsupials.1 The extant monotremes are the shortand long-nosed echidna and the platypus. The monotremes are egg-laying mammals that have relatively low but regulated body temperature (approximately 32C). They nurse their young from milk-secreting patches, rather than nipples and have thick fur. Their bone structure contains some reptilian characteristics, and genetic analysis indicates that they are more similar to reptiles and birds than other mammals. The platypus has a bill that responds to electric elds and a poison spur, characteristics typically seen in reptiles or sh but not in mammals. Despite the origin of monotremes early in the mammalian line, relatively little speciation has occurred, with only ve monotreme species known to have evolved, presumably because their geographic isolation from other species reduced evolutionary pressure.1 Thus the physiology of monotremes is likely to more closely resemble that of the rst mammals than any other mammals, and an early report that echidnas did not have REM sleep generated considerable interest.26,27 It suggested that REM sleep was a more recently evolved state with some higher cognitive function. Because of the possibility that a REM sleep-like state might be missed in the echidna, we reexamined this issue. In addition to recording electroencephalograms and electromyograms, we monitored brainstem neuronal activity.28 We know that

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FIGURE 9.1 Total sleep amounts and REM sleep amounts. Humans are not unusual either in terms of their total sleep or REM sleep amounts. (From Siegel J.M., The REM sleep-memory consolidation hypothesis, Science, 294, 10581063, 2001. With permission.)

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brainstem neuronal activity generates REM sleep29; therefore it might be possible to detect a REM sleep-like state in the echidna even if the forebrain EEG did not resemble that of REM sleep in placental mammals. We found that brainstem activity during sleep in the echidna did not resemble the activity seen in other mammals during non-REM sleep. Rather it resembled that seen in REM sleep (Figure 9.2). We concluded that echidnas did have a REM sleep-like state, but one that was not accompanied by low voltage cortical EEG as is seen in adult mammals. In this respect the REM sleep-like state resembled that of many neonatal animals, which have high voltage activity during periods of REM sleep. It has also been reported that a state looking like REM sleep, with low voltage EEG, may occur in echidnas.30 We saw no such state in our studies, and the Nicol et al. study did not demonstrate that the state they were observing was a sleep state, rather than a quiet waking state, so further investigation of this issue may be warranted. Both studies agree, however, that the echidna has a REM sleep-like state, in contrast to the earlier work. Because we saw a state that resembled REM sleep in the echidna, we next studied sleep in the platypus, which is considered the most primitive of the mammals.31 This raised special problems, because these animals are very delicate, are dangerous to handle because of their poison spurs, and are partially aquatic and cannot be housed in conventional cages. The platypus requires special animal husbandry procedures. Water pumps, needed to circulate water in their pool, generate large electrical elds, which stress and thereby can cause the death of the animals. Shielding procedures have to be used to minimize this stimulus. Telemetry, both on land and under water, is necessary to allow continuous recording. When we succeeded in recording from the platypus, we found that it has a particularly vigorous motor activation during sleep, equal to or greater than that of other mammals in REM sleep (Figure 9.3). A video of this can be viewed at our web site http://www. npi.ucla.edu/sleepresearch. When we calculated the amount of REM sleep, we were surprised to discover that the platypus had more REM sleep than any other animal, up to 8 hours per day. Both the echidna and platypus are extremely immature at birth, resembling a worm. They crawl out of the birth canal and into a pouch where they are protected, warmed, and nourished for several months. The high levels of REM sleep in monotremes strengthen the relation between immaturity at birth and REM sleep amounts in adulthood.

AQUATIC MAMMALS
Aquatic mammals have sleep patterns that are quite different from those in terrestrial mammals, so investigation of sleep in marine mammals may be instructive in understanding sleep as a whole, as well as the role of REM versus non-REM sleep. Under some conditions dolphins swim 24 hours a day for long periods. During their swimming they breathe regularly and are able to avoid the sides of the pool. Lilly rst noticed that dolphins often close one of their eyes but rarely close both. The signicance of this was discovered by Lev Mukhametov and colleagues, who developed reversible, relatively noninvasive techniques for recording EEG during swimming. They found that dolphins generated the high voltage EEG typical of nonREM sleep in either the right or left side of their cortex, but never in both sides.32

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FIGURE 9.2 Instantaneous rate plots of medial reticular neurons during sleep and waking states. In the echidna, rate varies in a way resembling that seen in placental mammals during REM sleep, rather than that in the regular manner of non-REM sleep. (From Siegel J.M., Manger P., Nienhuis R., Fahringer H.M., Pettigrew J., The echidna Tachyglossus aculeatus combines REM and non-REM aspects in a single sleep state: implications for the evolution of sleep, J. Neuroscience, 16, 35003506, 1996. With permission.)

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FIGURE 9.3 Sleep states in the platypus. The platypus has periods of rapid eye movements during a state characterized by high voltage EEG. (From Siegel J.M., Manger P.R., Nienhuis R., Fahringer H.M., Shalita T., Pettigrew J.D., Sleep in the platypus, Neuroscience 91, 391400, 1999. With permission.)

The same unihemispheric sleep has now been seen in several cetacean species.33 Figure 9.4 shows an EEG recording we carried out in a beluga whale. USWS appears to be at least partially an adaptation to the complex brain activity required for breathing in the dolphin. In contrast to other animals that breathe automatically during sleep, dolphins and other cetaceans need to be at the surface to breathe, need to sense wave action, and minimize water ingestion during breathing movements. Administration of light doses of barbiturates to dolphins will stop breathing (long before it produces effective analgesia). This is quite different from terrestrial mammals that breathe and regulate blood gasses effectively even when deeply anesthetized. In the dolphin the optic chiasm is completely crossed so that all visual input to each hemisphere comes from the opposite eye. Because visual input can block certain

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EEG rhythms,34 it is necessary to determine if any EEG change observed contralateral to a closed eye is secondary to the reduction of visual input. Generally the eye contralateral to the hemisphere that was sleeping was closed, as one would expect, because it is unlikely that visual input could be effectively processed in the hemisphere with EEG synchronization; however we also demonstrated that eye closure was not the cause of the high voltage EEG Closure or covering of one eye did not necessarily produce high-voltage activity in the opposite hemisphere. Conversely we noted that the eye opposite the sleeping hemisphere could open without blocking the high voltage EEG33; therefore the EEG-dened sleep state is not simply a consequence of reduced visual input to the contralateral eye. A similar control for vision-related EEG changes has not been done to support claims of USWS in birds, who in any case show relatively subtle differences between the EEG in the two hemispheres, consistently detectable only with power spectral analysis,35 in contrast to the USWS visible in cetaceans. If one hemisphere is prevented from showing high-voltage EEG by gently stimulating dolphins, a rebound of sleep in the deprived hemisphere is seen when deprivation stops,36 important evidence that sleep debt can be localized to one hemisphere. Despite many studies, no convincing evidence of REM sleep in dolphins or any other EEG instrumented cetacean has been produced. The absence of such evidence may result from the conditions under which these observations have been made. Often the animals are restrained during recordings. In those cases where they have been unrestrained, the stimulation caused by the recording cable may have prevented appearance of REM sleep but, considering the strong REM sleep pressure shown by all terrestrial mammals that have been deprived and that allows high levels of REM sleep even under uncomfortable sleeping conditions, one would expect that some unequivocal REM sleep would have been seen even under less than natural conditions. One can conclude that if REM sleep exists in the dolphin, REM sleep amounts are among the smallest of any mammal or are uniquely sensitive to disturbance. A more subtle issue is whether REM sleep may take some novel form in dolphins that has escaped detection. An alternate hypothesis is that unihemispheric slow-wave sleep may eliminate the need for REM sleep; for example, if REM sleep has evolved to stimulate brainstem areas after non-REM sleep to allow optimal functioning in subsequent waking, the presence of virtually continuous brainstem activity required for the continuous movement and breathing shown by dolphins may make REM sleep unnecessary.

REPTILES
The presence of REM sleep in large amounts in the most primitive mammals and in birds suggests that it may have been present in a common ancestor of these two classes of animals. That would indicate that at least some reptiles have REM sleep. The alternate theory, that REM sleep evolved twice, once in mammals and once in birds, suggests that a REM sleep precursor state must have existed in pre-avian, premammalian reptiles. According to both hypotheses, examination of state organization in reptiles would provide an insight into the primitive aspects of REM sleep. The key challenge is devising a method that would be effective in detecting such a

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state. To do this we decided to follow the approach we used in the echidna. Because we knew what the pattern of brainstem neuronal activity is in the mammalian REM sleep state, and because midbrain and pontine brainstem regions are both necessary and sufcient for generating the major neurological changes seen in REM sleep,29 we decided to conduct the rst investigations searching for aspects of REM sleep at the neuronal level in reptiles.37 We chose the turtle as a representative reptile because excellent prior behavioral studies had been conducted on these animals7 and because they adapted well to the laboratory.

FIGURE 9.4

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At the neuronal level, there are two consistent brainstem activity changes underlying REM sleep. One is the burst-pause discharge pattern that gives rise to the rapid eye movements and twitching characteristic of REM sleep. This pattern is present in most medial reticular neurons and therefore should be relatively easy to detect. The second is the cessation of release of norepinephrine, serotonin and histamine during REM sleep. This would be much more difcult to detect, because these monoaminergic cell groups are intermingled with other cell types and there is no easy way to determine the transmitter phenotype of any recorded cell. Our immunohistochemical analyses showed, however, that these cell groups were present in the turtle, so we focused our effort on recording neuronal activity from medial reticular cells during quiescent states, expecting to record from non-monoaminergic and possibly monoaminergic cells. Our results were clear. We saw no acceleration of discharge and no burst-pause pattern of discharge analogous to that seen in mammalian reticular cells during sleep. It appears that this aspect of REM sleep is not present in any form in turtles. We do not know the pattern of discharge of monoamine cells in the sleep of the turtle, and it is possible that a cessation of discharge occurs during behavioral immobility. However, we did not see cells that had the tonic waking discharge with cessation of discharge within the sleep period even though some of the neurons we recorded were within the serotonergic raphe region. Further investigations are necessary to test for this possibility. What we can conclude is that the periodic occurrence of brainstem activation that is so characteristic of REM sleep in terrestrial mammals is absent in the turtle. REM sleep precursor states may be present in the reptilian species that gave rise to mammals and birds but not in modern day turtles. Alternatively the phasic motor activation seen in REM sleep may have evolved rapidly at the onset of the avian and mammalian lines, perhaps in relation to homeothermy.

FIGURE 9.4 (See facing page.) Relationship between EEG and the state of eyes in a beluga whale. (A) The state of eyelids and EEG spectral power (13 Hz; 5-sec epochs) from the two hemispheres (R, right; L, left) in a white whale recorded over a 3-h period. EEG power was normalized as a percentage of the maximal power in each hemisphere during this period. The state of each eye (R, right; L, left) was scored in real time (O, open; I, intermediate; or C, closed) and then categorized for 5-sec epochs as described. Compressed gure does not show short-lasting changes in eye state. (B) Expansion of the two 2.5-min recordings of the EEG and the state of both eyes. The examples show the EEG asynchrony and parallel changes in eye state recorded in this whale at the times marked as 1 and 2 in Figure 4 A. Note that the EEG does not change immediately with changes in eye position. The right eye did not close during episode 1, and the left eye did not close during episode 2. (C) The average EEG spectral power in the two hemispheres during episodes with unilateral eye opening (LO/RC, left open and right closed; LC/RO, left closed and right open). EEG power was normalized as a percentage of the average 13 Hz power recorded in each hemisphere during SWS with the contralateral eye closure. Reported values are the means S.E. (LO/RC, n = 238 epochs; LC/RO, n = 441 epochs). (From Lyamin, O.I., Mukhametov, L.M., Siegel, J.M., Nazarenko, E.A., Polyakova, I.G., and Shpak, O.V., Unihemispheric slow wave sleep and the state of the eyes in a white whale, Behavioral Brain Res., 129, 125, 2002. With permission.)

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CONCLUSIONS
The ultimate question for sleep researchers is the function of REM and non-REM sleep. Phylogenetic evidence constrains any theory attempting to answer these questions. We know that sleep amounts vary by more than an order of magnitude across mammalian species. Either the amount of time spent sleeping has no relation to underlying function, which would distinguish sleep from many other homeostatically regulated processes, or sleep need varies considerably across species. The correlates of this variation should provide some insight into sleep functions. A survey of the available data indicates that phylogenetic order does not explain much of the variation of sleep time across species. There is extensive overlap of both REM and non-REM sleep time between orders, despite the genetic, anatomical, physiological, and behavioral commonalities within order. Prior data and new data on primitive mammals and cetaceans indicate a strong negative correlation between total sleep time and weight. Because metabolic rate is strongly and negatively correlated with body mass, this is also a positive correlation between metabolic rate and sleep time. Some evidence suggests that brain regions with high metabolic rate have higher levels of sleep deprivation-induced damage. We hypothesized that sleep serves to repair damage caused by oxidative stress.38,39 REM sleep amounts are positively correlated with non-REM sleep amounts, suggesting that REM sleep may work in concert with non-REM sleep. One persistent hypothesis that has been raised in several forms is that REM sleep serves to stimulate the brain to prepare for waking after a period of non-REM sleep.23,40,41 Most of the variation in REM sleep amounts is independent of non-REM sleep duration. The phylogenetic data indicate that animals born in a relatively immature state have more REM sleep early in development. One may hypothesize that in these immature animals REM sleeps activation of the brain facilitates development. In animals that are more mature at birth, this process may have occurred in utero and continued postnatally in their direct interactions with the environment in waking. Immature animals are obviously not able to interact with the environment in the same way. A major mystery that remains is why immaturity at birth should be correlated with REM sleep time in adulthood. Marine mammals have sleep patterns that differ greatly from those seen in other animals. They show unihemispheric sleep, with both hemispheres never being in deep sleep at the same time. They can sleep while swimming, apparently controlling muscles bilaterally. Finally, they appear to have little or no REM sleep. Understanding the mechanisms and functional relations underlying these unusual sleep adaptations of marine mammals can offer a major insight into the function and mechanisms of sleep.

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