Chapter 7 the Phylogeny of Sleep

Chapter 7 The phylogeny of sleep

KRISTYNA M. HARTSE * Sonno Sleep Center, El Paso, TX, USA

INTRODUCTION the extent to which definitive statements can be made about the origin of sleep. However, by studying living, Why do we sleep? Despite a voluminous body of scien- phylogenetically ancient organisms such as insects, tific and clinical literature, the definitive answer to this fish, amphibians, reptiles, and primitive mammals, fundamental question has yet to be found. To the clues to the function of sleep might be revealed. insomnia patient with unrelenting chronic sleepless- This phylogenetic approach to investigating the ori- ness, the answer is painfully and viscerally obvious. gins of sleep has not been without controversy, and Sleep prevents feelings of sleepiness and dysphoria there is disagreement in the literature about the pres- during the day. To the scientist and clinician, however, ence or absence of sleep in nonmammals. There is gen- this answer, although responsive to the universally eral agreement that most nonmammalian organisms acknowledged effects of sleep loss, does not address exhibit behavioral sleep or rest. However, the electro- the specific biological or functional reasons for sleep physiological signs of sleep in nonmammalian organ- (Rechtschaffen, 1998). isms may be very different from that of mammals. All mammals and birds studied to date exhibit This observation has led some authors to conclude that, unambiguous signs of sleep. Furthermore, an array of by definition, nonmammalian species do not sleep specific human sleep disorders, including sleep apnea, because mammalian electrophysiological correlates of narcolepsy, periodic limb movements, restless legs, sleep are not present (Walker and Berger, 1973). These and insomnia, correlate with deficits in health and issues will be reviewed as we examine evidence for the well-being. These consequences of disturbed sleep in origins of sleep. conjunction with the universality of sleep in mammalian organisms imply that sleep serves an important THE DEFINITION OF SLEEP life-enhancing or even life-sustaining function. Corre- lations, however, do not prove causality. Whether the Sleep is defined by both behavioral and electrophysio- function of sleep can be discovered by studying human logical criteria. The well-established behavioral criteria sleep disorders or more generally by studying neuro- include: (1) a species-specific posture; (2) behavioral logically and biochemically complex mammalian spe- quiescence; (3) elevated arousal thresholds; and (4) cies is questionable. rapid state reversibility with moderately intense stimu- A different approach to discovering the origins and lation to distinguish sleep from hypothermia, torpor, or functions of sleep would be through the study of non- coma (Flanigan et al., 1974). Sleep homeostasis, the mammalian organisms which have remained relatively compensatory rebound in sleep after deprivation of unchanged from their ancient fossil ancestors and quiescent states, is an additional feature in the defini- which may provide clues about the origins of sleep. tion of sleep (Tobler, 2005). In mammals and birds, The presence of behavioral and electrophysiological there are distinctive electrophysiological correlates that signs of sleep in living mammals and birds suggests accompany behavioral sleep. As a result of the close that sleep has been perpetuated in evolution from relationship between behavior and electrophysiology, ancient origins. A behavior such as sleep, of course, electrophysiological correlates are almost universally does not leave a fossil record, which severely limits substituted for behavioral observation to define the

*Correspondence to: Kristyna M. Hartse, Ph.D., Clinical Director, Sonno Sleep Center, 1400 George Dieter, Suite 210, El Paso TX 79936, USA. Tel: 915-533-8499, E-mail: [email protected] 98 K.M. HARTSE presence of sleep. Slow-wave sleep (SWS) is marked by findings have suggested that the spikes are a nonmam- high-amplitude neocortical slow waves. Cyclically alter- malian electrophysiological correlate of SWS. Persua- nating with SWS is rapid eye movement (REM) sleep sive evidence for REM sleep in nonmammalian (also called paradoxical sleep), characterized by low- organisms is not strong. Because the appearance of the voltage brain activity similar to that of waking, skeletal reptilian spike is substantially different from the neocor- muscle inhibition, and REMs. Although the distribu- tical slow waves recorded in mammals (Figure 7.1), tion and amounts of non-REM (NREM) and REM these findings have led some investigators to conclude sleep vary widely among mammals and birds (Zeplin that the spike is not an electrophysiological marker of et al., 2005), the electrophysiology of these two states sleep (Walker and Berger, 1973). Further studies in the is well established except in cetaceans (whales and rat and cat, however, have revealed the presence of a dolphins) and a monotreme, the echidna, a primitive spike recorded from the ventral hippocampus (VH) dur- egg-laying mammal (Mukhametov, 1987; Siegel et al., ing SWS which is similar to the reptilian spikes (Metz 1996; Lyamin et al., 2002, 2004, 2005). and Rechtschaffen, 1976; Hartse et al., 1979). VH spikes The electrophysiological correlates associated with and reptilian spikes have a similar morphology: they both nonmammalian behavioral sleep have received consid- show a rebound following enforced wakefulness, erable attention. No change in brain activity during and they both respond similarly to pharmacological behavioral quiescence, slow waves during waking agents. Additional support for a relationship between which diminish with behavioral sleep, both the presence hippocampal spikes and neocortical slow waves is the and absence of SWS, and both the presence and finding that hippocampal sharp waves are modulated absence of REM sleep have all been reported. How- by neocortical activity during SWS (Sirota et al., 2003). ever, some of the most rigorous studies, particularly The generation of slow waves requires neocortical in reptiles, have revealed the presence of a high-voltage development, and slow-wave activity recorded from spike which is prominent during behavioral sleep brain surface electrodes is easily observed in mammals and minimally present during behavioral wakefulness that have extensive neocortical development. However, (Flanigan, 1973, 1974; Flanigan et al., 1973, 1974). The the rudimentary neocortex of fish, amphibians, and spikes increase in a homeostatic response following reptiles in comparison to mammals would seem to pre- enforced wakefulness, and both spikes in reptiles and clude on anatomical grounds the observation of slow SWS in mammals respond similarly to pharmacological waves in these species (Nieuwenhuys, 1994). In addi- agents (Hartse and Rechtschaffen, 1974, 1982). These tion, it has recently been convincingly argued that the

CAT HIPPOCAMPUS

100 mv

HIPPOCAMPUS 1s 1s –INTEGRATION

TORTOISE

LIMBIC AREA

50 mv LIMBIC AREA 1s 1s –INTEGRATION

Fig. 7.1. Comparison of mammalian ventral hippocampus spikes in the cat with reptilian spikes in the tortoise. In each recording the upper tracing shows the raw, unfiltered record. The lower tracing shows the signal after it has been passed through a bandpass filter set for 30–1000 Hz, a 60-Hz notchfilter, and a Beckman 9852 integrator coupler. Both spikes are shown at slow and fast speeds. (Reprinted with permission from Hartse and Rechtschaffen, 1982.) THE PHYLOGENY OF SLEEP 99 presence of the mammalian neocortex per se is not neurochemical changes (Levenson et al., 1999). Using necessarily the most critical element in the electrophys- time lapse video, preliminary studies in the pond snail, iological expression of slow waves, but rather it is the Lymnaea stagnalis, have identified a resting state advanced development of palliopallial connectivity in which is associated with reduced responsiveness to mammals and birds which accounts for the presence an appetitive stimulus and an increase in quiescence of slow waves in these species (Rattenborg, 2006a). This following rest deprivation (R. Stephenson, personal position has also spurred debate (Rattenborg, 2007; Rial communication). et al., 2007b). In contrast to the findings of SWS asso- Two ocean-dwelling gastropods, the cuttlefish ciated with mammalian and avian quiescence, some (Sepia pharonis) and octopus (Octopus vulgaris), meet investigators have reported the presence of slow waves the criteria for behavioral sleep, and both exhibit during reptilian waking which diminish during behav- rebounds in behavioral sleep following periods of ioral sleep. This observation has been interpreted as sug- enforced wakefulness (Duntley et al., 2002; Brown gesting that reptilian wakefulness, and not reptilian et al., 2006). Electrophysiological recordings from sleep, is the precursor of mammalian SWS (De Vera above the vertical lobe in the brain of the octopus have et al., 1994; Rial et al., 2007a). This position, however, revealed trains of high-amplitude spikes associated has not been widely adopted based upon the preponder- with behavioral quiescence, suggesting a correspon- ance of evidence (Rattenborg et al., 2007). dence to the spikes observed during reptilian behav- As we can see, the task of identifying sleep in non- ioral quiescence (Flanigan, 1973, 1974). A recent study mammalian organisms has not been a straightforward in the crayfish (Procambarus clarkii) also documented one. Besides the imposition of mammalian criteria for clear signs of behavioral sleep as well as a rebound in sleep on nonmammalian organisms, additional con- recovery sleep following enforced wakefulness straints in studying nonmammalian species include tech- (Ramon et al., 2004; Mendoza-Angeles et al., 2007). nical difficulties in evaluating organisms which inhabit However, in contrast to findings in the octopus, contin- unusual arboreal or aquatic environments not conducive uous fast spikes occurred during behavioral wakeful- to electrophysiological recording, an absence of stereo- ness. With the onset of distinctive quiescent postures, taxic atlases to assure comparable electrode placements “continuous slow waves” in the 15–20-Hz bandwidth between species, and a sparsity of data which establish were observed. This frequency range is substantially homologous brain structures between mammals and higher than the 0.5–4.0-Hz frequency range typically nonmammals (Hartse, 1994). Nonetheless, even given associated with mammalian SWS. Thus, although these these constraints as well as the contradictory findings recent studies are in agreement about the presence of of nonmammalian studies, the most general conclusion behavioral sleep, there is significant divergence in the that can be made is that behavioral quiescence is a uni- electrophysiological findings. versal phenomenon in living organisms. INSECTS INVERTEBRATES Some of the most promising clues to the function of In comparison to the many studies on sleep in verte- sleep have come from a new and rapidly growing body brates, the literature on sleep behavior and electrophysi- of work on sleep in insects, specifically D. melanogaster ology in invertebrates, organisms without backbones, is (for a recent review, see, Hartse, 2009). In early observa- exceedingly sparse. The exception, as we shall see, is a tional studies both in the field and in the laboratory, growing body of work in insects, specifically the fruit wasps, bees, flies, butterflies, and moths were observed fly, Drosophila melanogaster, which suggests that these to exhibit state-reversible behavioral sleep associated organisms may serve as a model for studying the with species-specific postures as well as increased arousal molecular basis for mammalian sleep (Hendricks et al., thresholds (Rau and Rau, 1916; Andersen, 1968). The 2000b). honey bee (Apis mellifera) exhibits distinctive antennae Invertebrates which have been studied to date meet and head postures correlated with behavioral sleep and the behavioral criteria for a sleep-like state. The sea waking (Figure 7.2). During behavioral sleep decreases slug (Aplysia californica) exhibits periods of nocturnal in locomotor activity, decreases in thoracic temperature, behavioral quiescence and decreased motor activity decreases in neck muscle activity, and increases in thresh- (Strumwasser, 1971). In addition a rise in 5-hydroxy- olds to infrared stimuli are present (Kaiser, 1988). Follow- tryptophan (5-HT) secretion in the hemolymph during ing 12 hours of sleep deprivation, a significant increase the dark portion of the 24-hour cycle, corresponding to in antenna immobility in sleep-deprived as compared to periods of decreased locomotor activity, suggests that control bees is present in a homeostatic response to behavioral sleep is accompanied by mammalian-like deprivation (Sauer et al., 2004). The electrophysiological 100 K.M. HARTSE response to the administration of caffeine, metamphe- tamine, and modafinil whereas behavioral quiescence is induced following antihistamine administration (Shaw et al., 2000; Hendricks et al., 2003; Andretic et al., 2005). There are age-related changes across the lifespan with increased quiescence in immature organisms and a decline in quiescence as well as a fragmentation of rest periods with age (Shaw et al., 2000; Koh et al., 2006). A decrease in spike-like local field potentials with quiescence suggests an electrophysiological correlate of behavioral sleep (Nitz et al., 2002), and chemi- cal lesioning as well as stimulation of the mushroom bodies have identified a specific neuroanatomical locus for the control of sleep in the fly brain (Joiner et al., 2006; Pitman et al., 2006). Fig. 7.2. A quiescent bee. (Courtesy of Cheryl Moorehead.) One of the major advantages in utilizing Drosophila is its well-known genetic profile and the identification correlates of sleep in the bee are unknown, but single cell of mutant strains with specific alterations in normal recordings from directionally sensitive optomotor inter- patterns of quiescence (Cirelli, 2003; Kume et al., neurons reveal a circadian rhythmicity with decreased 2005). A mutation in the dopamine transporter gene sensitivity to a pattern stimulus at night, corresponding has been identified in a near-sleepless mutant ( fumin) to times of decreased locomotor activity and behavioral (Kume et al., 2005). Significantly increased motor sleep (Kaiser and Steiner-Kaiser, 1983). Delivery of a puff activity across the light–dark cycle independent of the of air reversed this decreased sensitivity, indicating neu- circadian clock, decreased arousal thresholds, and an ronal state reversibility. Three species of scorpion (Tobler absence of rebound in response to rest deprivation and Stadler, 1988)aswellasthecockroach(Tobler, 1983; were associated with normal lifespans and an absence Tobler and Neuner-Jehle, 1992) all meet the behavioral of obvious morphological, reproductive, or develop- criteria for sleep. A recent study in the cockroach mental abnormalities. Other mutant strains exhibiting (Stephenson et al., 2007) has elegantly demonstrated a reduced sleep amounts, however, also have decreased similarity to the results in mammals following sleep lifespans (Cirelli et al., 2005). These findings not only deprivation. Deprivation of cockroach behavioral quies- suggest an important role for dopamine in the control cence led to both an increased metabolic rate without a of sleep expression, but also that some forms of sleep- change in body mass and increased mortality in compari- lessness may have a genetic basis which is not neces- son to controls. These results are remarkably similar to sarily associated with adverse consequences for the findings of increased metabolic rate and increased survival. Recent studies of specific protein manipula- mortality in the rat following sustained sleep deprivation tions also suggest that Drosophila may provide new (Rechtschaffen and Bergmann, 2002). insights into the functional molecular basis of sleep The fruit fly, D. melanogaster, has been proposed as a (Foltenyi et al., 2007; Naidoo et al., 2007). model for the study of mammalian sleep, and the simila- In summary, quiescent states, which meet the cri- rities between characteristics of sleep in the fruit fly and teria for behavioral sleep, are present in invertebrate in mammalian species are striking (Hendricks et al., species. The electrophysiology of invertebrate sleep is 2000b; Cirelli, 2006). The well-studied genetic mapping, not well known, although there is evidence that distinc- the short life cycle which permits rapid assessment of tive electrophysiology may exist. In addition, studies in genetic manipulations in subsequent generations, and Drosophila are rapidly advancing understanding of the the relative ease of maintaining large experimental colo- detailed molecular and genetic structure of sleep nies make the fruit fly an excellent candidate for studying mechanisms that may provide fruitful clues to sleep the molecular and genetic aspects of sleep. function in mammals. Initial studies provided convincing evidence that behavioral rest in Drosophila is analogous to mamma- FISH AND AMPHIBIANS lian sleep (Hendricks et al., 2000a; Shaw et al., 2000). Similar to mammals, Drosophila exhibits increased Behavioral sleep has been described in both fish and arousal thresholds and an increase in quiescence fol- amphibians. Very few electrophysiological studies have lowing enforced wakefulness that is independent of been conducted in these organisms primarily as the the circadian clock. Behavioral wakefulness occurs in result of significant technical problems in obtaining THE PHYLOGENY OF SLEEP 101 reliable recordings in an aquatic environment. Several plays a major role in the regulation of mammalian species of Bermuda reef fish and freshwater fish sleep and wakefulness, and hypocretin deficits are (Peyrethon and Dusan-Peyrethon, 1967; Siegmund, 1969; now well known to be the major neurochemical defect Tauber and Weitzman, 1969; Shapiro and Hepburn, in patients with narcolepsy (for a review see Mignot, 1976; Tobler and Borbely, 1985) exhibit behavioral sleep. 2005). In contrast to narcoleptic patients who exhibit Eye movements have been observed during periods of excessive daytime sleepiness and cataplexy (a sudden behavioral quiescence in Bermuda reef fish, suggesting loss of muscle tone in response to emotional stimuli), the presence of REM sleep (Tauber and Weitzman, mutant zebrafish lacking the hypocretin receptor did 1969). Other studies, however, have failed to replicate not demonstrate an increase in daytime sleep or the this finding (Peyrethon and Dusan-Peyrethon, 1967; development of cataplexy-like behaviors. They did, Shapiro and Hepburn, 1976), leading these authors to however, exhibit an increase in nocturnal sleep–wake conclude that REM sleep is not present in these species. transitions and an increase in nocturnal sleep fragmen- There is evidence for a rebound in resting behavior fol- tation. Although zebrafish hypocretin receptors were lowing enforced behavioral wakefulness in the perch not found in proximity to the monoaminergic neuro- (Cichlosoma nigrofasciatum) and goldfish (Carassius transmitter systems regulating mammalian sleep and auratus), indicating the presence of homeostatic regulat- waking, these receptors did colocalize with GABAergic ing mechanisms, similar to those in mammals (Tobler neurons in the anterior hypothalamus, suggesting that and Borbely, 1985). these neurons rather than monoaminergic systems are An emerging body of work has suggested that the important for sleep regulation in zebrafish. This study zebrafish, Danio rerio, may also serve as a model is of significance not only because it suggests that the organism for understanding the genetic and molecular zebrafish may be an important organism for under- regulation of sleep. Zebrafish meet the criteria for standing the underlying molecular basis of sleep, but behavioral sleep, and in addition, quiescent states are also that nonmammalian species must be meticulously induced by sleep-promoting substances such as melato- evaluated, using rigorous methodology, since there nin, diazepam, and sodium pentobarbital (Zhdanova may be important and significant differences which et al., 2001). Genetic and immunohistochemistry stud- limit the generalization of findings to mammals. ies demonstrate that the cholinergic, aminergic, and The evidence for electrophysiological correlates of orexin/hypocretin systems of the zebrafish show striking sleep in fish is meager. Recordings in the tench (Tinca similarities to mammals (Zhdanova et al., 2001; Kaslin tinca) did not reveal distinctive electrophysiology asso- et al., 2004; Prober et al., 2006). However, a recent ciated with behavioral sleep (Peyrethon and Dusan- detailed study also suggests important differences Peyrethon, 1967). Slow waves with superimposed between sleep in zebrafish and sleep in mammals spike-like activity occurring during behavioral sleep (Yokogawa et al., 2007). The behavioral characteristics have been observed in the catfish (Karmanova and of sleep in zebrafish were observed in this study, but Lazarev, 1978). Neither of these studies reported the homeostatic response to sleep deprivation exhibited electrophysiological evidence for REM sleep. striking differences in comparison to mammals. Follow- Also of note are descriptions of “sleep swimming” ing 6 hours of sleep deprivation induced by electrical zooplanktivorous fish which increase the frequency stimulation, there was an expected rebound in quies- of nocturnal dorsal, pectoral, and caudal fin strokes cence when fish were released into darkness at the while maintaining a stereotypic nocturnal position in end of the deprivation period. However, sleep-deprived the coral reef (Goldshmid et al., 2004). The measurable fish which were released into light following depriva- beneficial effects to the coral reef resulting from this tion did not exhibit a homeostatic sleep rebound. Also behavior include enhanced water replenishment and of note is that there was virtually a complete suppres- increased oxygenation. It could be argued that, by def- sion of sleep by maintaining the zebrafish under condi- inition, behavioral sleep is not present in these fish tions of constant illumination. No sleep rebound since they are obviously not quiescent. On the other occurred following this light-induced sleep suppres- hand, the increased activity of nocturnal fin move- sion, but sleep gradually reemerged after several days. ments occurring with a stereotypic body posture may This suppression of sleep under conditions of constant be a unique variation on quiescent behavior. Such illumination may be similar to the marked decrease in unique manifestations of “nonquiescent sleep” could sleep which occurs in migrating birds (Rattenborg also exist in other organisms which have been judged et al., 2004; Rattenborg, 2006b). In contrast to mam- as not exhibiting sleep by current definitions. mals, there was not a close localization between either The amphibians are of interest because they repre- larval or adult zebrafish hypocretin receptors and the sent the basal stock from which land vertebrates monoaminergic and cholinergic systems. Hypocretin developed (Romer, 1966). Detailed sleep studies in 102 K.M. HARTSE

Fig. 7.3. A sleeping frog. (Courtesy of Roy Smith.)

Fig. 7.4. An American alligator dozing in late afternoon. amphibians are sparse, and reports of electrophysiolog- (Courtesy of Kristyna M. Hartse.) ical correlates associated with sleep-like states have, once again, been variable. Clear signs of behavioral these findings, no signs of behavioral or electrophysio- sleep were not observed in either the bullfrog, Rana logical sleep, independent of ambient temperature, catesbiana, or the western toad, Bufo boreas (Hobson, were found in the American alligator (Alligator missis- 1967; Huntley et al., 1978)(Figure 7.3). However, the sipiensis)(Van Twyver, 1973)(Figure 7.4). SWS, but tree frog, Hyla squirella and H. cinerea, exhibited not paradoxical sleep, has been reported to occur in signs of behavioral rest, but distinctive electrophysiol- the caiman (Warner and Huggins, 1978; Meglasson ogy associated with this behavioral rest was not pre- and Huggins, 1979). Although spikes and sharp waves sent (Hobson et al., 1968). Slow waves in the South were observed in this study, this electrophysiology American toad and spike-like activity in the frog was not correlated with degrees of progressive postural R. temporaria during behavioral sleep have both been relaxation. Behavioral quiescence associated with high- reported (Segura, 1966; Lazarev, 1978). Similar to some amplitude electrical activity that disappeared with studies in frogs, no distinctive electrophysiological cor- behavioral waking has been reported in a snake, relates of behavioral sleep have been found in the Python saebe (Peyrethon and Dusan-Peyrethon, 1969). salamander, and variations in heart rate did not corre- Findings in other reptiles have been equally diverse. late with activity and inactivity (McGinty, 1972). How- SWS has not been reported in lizards (Figure 7.5), but ever, spectral analysis did reveal electroencephalogram two studies have suggested the presence of paradoxical frequency increases during arousal (Lucas et al., 1969). sleep alternating with periods of quiet sleep not In summary, the data from amphibian studies are quite marked by slow waves (Tauber et al., 1968; Ayala- variable, but support the existence of behavioral sleep Guerrero and Mexicano, 2008). In iguanas, spikes and with possible electrophysiological correlates.

REPTILES

The first stem reptiles from which modern reptiles origi- nated are seen in the fossil record during the carbonifer- ous period approximately 30 million years ago (Romer, 1966). Reptilian sleep has been more extensively studied than sleep in most other nonmammalian species. Although there is general agreement that reptiles exhibit signs of behavioral sleep and wakefulness, the electrophysiological findings and their interpretation have been variable and often in sharp disagreement. In the caiman (Caiman sclerops), behavioral quiescence accompanied by high-voltage spiking, which disappeared during behavioral waking, was first reported by Flanigan et al. (1973). There was no convincing evi- Fig. 7.5. A monitor lizard sleeps on a branch. (Courtesy of dence for SWS or paradoxical sleep. In contrast to Kathleen Andersen.) THE PHYLOGENY OF SLEEP 103 sharp waves occurring during behavioral quiescence and (Hartse, 1994). Some may be due to true species differ- disappearing during behavioral waking have been docu- ences. Some may be due to variations in the meticulous- mented (Flanigan et al., 1973). Turtles and tortoises also ness and consistency with which recording procedures exhibit spikes during behavioral sleep which disappear were performed. Some may be due to the biased impo- during behavioral wakefulness. A rebound in spikes sition of mammalian criteria for sleep on nonmamma- occurred following enforced wakefulness. There was lian organisms which have a very different palette of no convincing evidence, however, for the presence of electrophysiology and behavior from that of mammals. either SWS or paradoxical sleep in turtles and tortoises However, the most persuasive evidence supports the (Flanigan, 1974; Flanigan et al., 1974). Further supporting presence of behavioral sleep with an electrophysiological the position that reptiles do not exhibit REM sleep are correlate, the high-amplitude spike, in reptiles. single-unit studies in the brainstem of freely moving turtles (Eiland et al., 2001). Bursting patterns character- BIRDS AND MAMMALS istic of reticular formation neurons in the mammalian brainstem were not observed during behavioral quies- In contrast to invertebrates and nonmammalian verte- cence, nor were cyclically occurring periods of eye brates, sleep in birds and mammals has been studied movements and phasic muscle bursts typical of mam- extensively (for reviews, see Amlander and Ball, malian REM sleep. 1994; Zeplin et al., 2005). Birds exhibit both SWS and Pharmacological studies in the tortoise, demonstrating paradoxical sleep, although paradoxical sleep differs a similar response of the reptilian spike and the cat VH from mammalian paradoxical sleep in that it occurs spike to amphetamine, Nembutal, parachlorophenylala- as short bouts lasting from a few seconds to a few nine, and alpha methyl-tyrosine do, however, indicate a minutes in duration. It is also well known that, unlike similarity between the reptilian spikes and mammalian most mammals, with a few exceptions described SWS (Hartse and Rechtschaffen, 1982). In another study below, birds exhibit unihemispheric SWS, i.e., one high-voltage spike activity was associated with behavioral hemisphere shows clear SWS and the other hemisphere quiescence in the tortoise, but the lack of the spike’s asso- exhibits clear waking with eye closure contralateral to ciation with elevated arousal thresholds in this study as the sleeping hemisphere. It has been proposed that uni- well as the modulating effect of temperature upon the hemispheric sleep may have evolved in response to the presence of the spike led these investigators to conclude risk of predation by allowing parts of the cerebrum to that the spikes are not an electrophysiological manifesta- be differentially alert (Lima et al., 2005). tion of “true” sleep (Walker and Berger, 1973). In con- The question of whether migrating birds sleep has trast, only mammalian-like SWS, but not paradoxical recently received attention (Rattenborg, 2006b). Migra- sleep, has been reported in the tortoise, Testudo margin- tions occurring over a period of several days suggest ata (Hermann et al., 1964), and both SWS and paradoxical either that birds sleep in flight or that sleep requirements sleep have been reported in the European pond turtle, are drastically reduced during this time. No electrophys- Emys orbicularis,aswellasinthetortoise,Gopherus fla- iological recordings of sleep have been made during vomarginatus (Vasilescu, 1970; Ayala-Guerrero et al., actual migration. However, in the laboratory, the white 1988). No electrophysiological correlates of behavioral crowned sparrow, a migrating songbird, spends 63% sleep and wakefulness as well as an absence of a homeo- less time sleeping during the migratory season as com- static response to enforced waking in the sea turtle, Car- pared to the no-migratory season (Rattenborg et al., etta caretta L., led to the conclusion that this species does 2004). As pointed out by Rattenborg (2006b),bystrict not sleep (Susic, 1972). Finally, observations of high- definition birds in flight do not sleep because they are amplitude slow-wave activity during waking in the lizard not quiescent, even though it seems unlikely that sleep have prompted one group of investigators to conclude does not occur for several days. Avian unihemispheric that reptilian waking is the precursor to mammalian SWS may allow some sleep in flight, but it seems SWS (Rial et al., 2007a). unlikely that REM sleep, which is typically sensitive to The often contradictory findings in the reptile liter- environmental disruption, occurs under these conditions. ature have raised an important issue. If REM sleep is The finding that sleep amounts are drastically reduced absent in reptiles, this suggests that REM may not have during the migratory season suggests that birds may been present in stem reptiles ancestral to birds and have a periodically reduced sleep need in response to mammals and as a result REM sleep may have evolved the demand of migration (Rattenborg, 2006b). Further independently in birds and mammals rather than being research with new technologies that permit in-flight perpetuated from a common ancient ancestor. There electrophysiological recordings is clearly required to are a number of parameters that could account for resolve the question of whether or not birds sleep in the differences in findings from the reptile studies flight (Figures 7.6 and 7.7). 104 K.M. HARTSE of NREM and REM sleep in both birds and mammals is of interest since the absence of REM sleep in reptiles would suggest that REM sleep is a more recent development in the phylogenetic history of land-dwelling organisms. Utilizing data primarily from mammals, several different theories have been advanced to explain the function of sleep. Some of the most persuasive data support an energy conservation hypothesis, and there is a positive correlation between basal metabolic rate (BMR) and total sleep time (Zeplin and Rechtschaffen, Fig. 7.6. A sleeping water fowl. (Courtesy of Berit Watkin.) 1974; Zeplin et al., 2005). That is, animals with higher metabolic rates spend more time asleep. However, recent path model analyses have found a significant negative correlation between BMR and total sleep time in mammals (Lesku et al., 2006). In contrast to the mammalian data, similar path model analyses in birds have not revealed a relationship between BMR and either SWS or REM sleep. The only statistically significant relationship in avian species was an inverse relationship between SWS time and risk of predation, suggesting different, independently evolved functions for sleep in mammals and birds (Roth et al., 2006). It has also recently been proposed that “mammalian sleep has no function apart from the rest of simple organisms” (Rial et al., 2007a). Although the simplicity of this theory is attractive, there is meager support for Fig. 7.7. Dozing flamingos. (Courtesy of Kathleen Andersen.) this position when the totality of data from phylogenetic studies is examined (Rattenborg et al., 2007). Fur- thermore, a recent metabolic study in the desert The features of sleep in mammals are well known iguana, Dipsosaurus dorsalis, supports the position through the use of a wide variety of electrophysiologi- that sleep contributes to energy conservation, even in cal and neurochemical techniques (for a review, see poikilothermic organisms (Revell and Dunbar, 2007). Zeplin et al., 2005). Like birds, mammals, with the Under controlled laboratory conditions, the mean met- exception of some cetaceans (whales and dolphins), abolic rate of sleeping iguanas was 27.6% less in comparison to waking across temperature ranges of exhibit both NREM and REM sleep in a predictable cyclically alternating fashion (Figure 7.8). The presence 20–40 C. However, a larger metabolic saving accrued during wakefulness at cooler temperatures than during sleep at warmer temperatures, suggesting that the energy conservation function of sleep in poikilotherms may be less significant than the impact of behavioral thermoregulation upon energy conservation. One group of animals which may shed light upon the origins of REM sleep are the living monotremes, primitive egg-laying mammals representing an early branch in mammalian evolution (Figure 7.9). The first study in the short-beaked echidna, Tachyglossus aculeatus, revealed the presence of NREM sleep, but unambiguous REM sleep could not be conclusively identified (Allison et al., 1972). More recent studies have utilized single-cell recordings from the echidna midbrain reticular formation and pons, structures known to have a distinctive bursting pattern of activ- Fig. 7.8. A sleeping lion. (Courtesy of Kathleen Andersen.) ity during REM sleep, to clarify whether or not REM THE PHYLOGENY OF SLEEP 105 REM sleep has been revealed in cetaceans, although jerking movements similar to the phasic twitches of mammalian REM sleep have been observed in the gray whale (Lyamin et al., 2000). It should not necessarily be concluded from these studies, however, that aquatic mammals do not have REM sleep. Current techniques for the detection of REM sleep in cetaceans may not be adequate or, alternatively, REM sleep in the aquatic environment may be present in a form different from that observed in terrestrial environments. Not only is the questionable absence of REM sleep in cetaceans different from sleep in land-dwelling mammals, the pattern of behavioral sleep and wakefulness in newborn cetacean calves is also different from Fig. 7.9. The short-beaked echidna in its Australian the young of land-dwelling mammals (Lyamin et al., habitat. (Courtesy of Ian Michael Thomas.) 2005). Unlike most mammalian infants which spend significant periods of the 24-hour-day sleeping, dolphin and killer whale neonates exhibited virtually no sleep is present in these organisms (Siegel et al., periods of behavioral rest or eyelid closure, which is 1996). A unique electrophysiological pattern of brain- correlated with the presence of sleep, for several stem unit discharge variability accompanied by high- months after birth. In concert with their infants, amplitude forebrain slow waves was observed (Siegel mothers also exhibited almost no resting behavior et al., 1996). This brainstem single-unit activity was for several months postpartum. These findings chal- not typical of the bursting pattern present in the mamma- lengetheconceptthatabasalamountofsleep,asit lian reticular formation during REM sleep, and phasic is currently defined by electrophysiological and motor activity or eye movements did not occur in concert behavioral criteria, is necessary for normal growth with this unit activity. These findings may be interpreted and development in all mammals. to support the hypothesis that sleep in the echidna is an amalgam of cortex-synchronized NREM and brainstem- THE PHYLOGENY OF SLEEP AND activated REM sleep which was subsequently differen- HUMAN SLEEP DISORDERS tiated during evolution into separate NREM and REM Phylogenetic sleep studies unquestionably provide states (Siegel et al., 1998). A subsequent study in the clues to our understanding of human sleep mechan- echidna has identified unambiguous REM sleep based isms, and more importantly, these data form a nexus upon the usual mammalian criteria for this stage (Nichol of evidence for ultimately understanding the function- et al., 2000). In contrast to these findings, the platypus ality of sleep in humans. How does the study of sleep (Ornithorhynchus anatinus), another monotreme, exhi- in organisms as diverse as the fruit fly and the whale bits abundant amounts of REM sleep characterized by contribute to our understanding of human sleep? muscle atonia, eye movements, and phasic twitching. Similar to the echidna, these elements of REM sleep Assessing the effects of sleep loss occurred in the presence of high-voltage slow waves (Siegel et al., 1999). Differences between the echidna Although the insomnia patient is frequently advised and the platypus in the expression of REM sleep may be that lack of sleep is not harmful or life-threatening, the result of adaptation to the vulnerability of their sleep- studies in Drosophila demonstrate that sleep loss can ing environments (Siegel et al., 1998). affect lifespan, aging, and gene expression (Cirelli, The only group of mammals in which REM sleep 2006; Koh et al., 2006). By extension, these findings has not been clearly identified is the cetaceans (whales imply that the impact of sleep loss in humans may and dolphins). Like birds, these mammals exhibit uni- have greater physiological significance than has been hemispheric SWS with eye closure contralateral to the previously appreciated. Epidemiological data support sleeping hemisphere (Mukhametov, 1987; Lyamin a correlation between shortened as well as extended et al., 2000, 2002, 2004). No arousal threshold studies sleep and decreased lifespan, indicating that less-than- have been performed, and a variable rebound in unihe- optimal sleep amounts are likely to be deleterious to mispheric sleep following unihemispheric sleep depri- longevity in humans (Kripke et al., 2002; Hublin vation has been reported in one study of the dolphin et al., 2007). There is also evidence that some strains (Oleksenko et al., 1992). No evidence for unambiguous of genetically short-sleeping Drosophila, akin to the 106 K.M. HARTSE normal human “short sleeper,” do not experience dele- rigorous and innovative neurophysiological and molec- terious effects of sleep loss such as decreased longev- ular methodologies which have been applied to the ity (Kume et al., 2005), although other studies have study of mammalian sleep must also be applied to non- demonstrated decreased longevity in short-sleeping mammalian species. Conversely, the application of flies (Cirelli, 2006). 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