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Keeping cool: a hypothesisabout the mechanismsand fundions of slow-wavesleep Dennis McGinty and Ronald Szymusiak regulatory and homeostatic model. As a thermoregulatory process, SWS incorporates usual heat loss processes, e.g. reduced heat production, cutaneous vasodilation, or sweating. But sleep is distinctive in certain ways: (1) sleep-related cooling can be delayed and integrated with circadian rhythms; (2) the reduced heat production is facilitated by the complete behavioral suppression associated with sleep, and (3) brain cooling is augmented by coincident reduction of cerebral metabolic rate. These concepts apply to SWS, which is usually defined by high amplitude synchronized cortical EEG patterns in conjunction with behavioral inactivity. This would include stages 2, 3, and 4 sleep in humans. The term SWS is sometimes given to stages 3-4 of human sleep, but we use the term as it is applied to all mammals and birds. Slow wave EEG activity is a convenient marker for sleep, and, through quantification of EEG wave frequency and amplitude, can indicate the intensity or 'depth' of sleep. However, use of the term SWS does not imply Mammalian sleep shares several properties with that EEG activity, per se, is the essential element of homeostatic behaviors such as feeding and drinking the sleep process. Indeed, we argue here that one including: (I) relatively constant daily consumption; possible essential element is brain temperature. Mammalian and avian sleep also includes 5-45% (2) increased 'appetite' (sleepiness) during forced sleep deprivation; (3) compensatory 'rebound' (depending on species) of rapid eye movement increases in consumption after deprivation is ended, (REM) sleep. During REM sleep, brain temperature and (4) at least in some species, death after about rises episodically in most species, but it falls again 2-3 weeks of complete deprivation ~,2. Thus, sleep during subsequent SWS episodes. Both the therappears to have one or more essential homeostatic moregulatory aspects9,1° and neural control 1 of functions. However, there have been few hypoth- REM are very different from those of SWS. For the eses about feedback mechanisms mediating sleep sake of brevity, these will not be discussed here. homeostasis. An understanding of the regulated feedback signal of a physiological control system is Brain and body coolingduring SWS A thermoregulatory process may be defined by an important for the study of the system, as demonstrated by the central role of experimental manipu- appropriate pattern of thermoregulatory effector lations of blood gases, blood pressure, and blood activation that occurs in response to a thermal nutrients and electrolytes in the study of the stimulus (heat or cold), and which is regulated by a corresponding homeostatic systems. The lack of predictable control system. This definition applies to such a concept for sleep is clearly among the SWS. Operationally, SWS can be characterized as an integrated thermoregulatory cooling process in that basic gaps in our understanding of physiology. Recent evidence derived from a variety of onset of sleep evokes reduced metabolic rate and methods has led us to develop a new hypothesis heat loss via vasomotor and sudomotor activation, about a physiological control of slow-wave sleep and because SWS can be an immediate or delayed (SWS) and related hypotheses about the neural response to an increase in brain or whole body mechanisms regulating sleep3. This evidence sug- temperature. Sleep onset has been shown to be gests that SWS is controlled, in part, by thermoregu- associated with decreases in body and/or brain latory mechanisms, and that an essential physiologi- temperature in several species. In humans and rats, cal feedback provided by SWS is brain or body this decrease can be independent of the circadian cooling. Thermoregulatory aspects of SWS have temperature rhythm 8,11, and in humans, it is indebeen recognized previously by several pendent of reductions in motor activity with sleep12. investigators 4-8, and Obal has suggested that heat In dolphins, which exhibit unihemispheric sleep, loss during SWS contributes to an energy-conserv- brain temperature drops selectively in the sleeping ing function of this state. Our hypothesis extends hemisphere ~3. It is possible to demonstrate SWSthese views to form a more comprehensive neuro- related increases in heat loss effector processes

DennisMcGintyand Current evidencesupports a hypothesis that slow-wave sleep(SWS) Ronald5zymusiakare in mammalsand birds is controlled by thermoregulatorymechanisms, at the 5epulveda and provides brain and body cooling as a primary homeostatic Veterans feedback process. Recent work has identified a media/preoptic area Administration anterior hypothalamic and basal forebrain neuronal network which Medical Center, Sepulveda,CA integrates thermoregulatory and hypnogenic controls. This network 91343, USAand the ind,lces EEGand behavioral deactivation, in part, through suppression Departmentof of the reticular activating system. Studieshave shown that SWS, like Psychology,UCLA, other heat loss processes, is facilitated when brain temperature LosAngeles,CA exceeds a threshold level. This threshold is hypothesized to be 90024, USA. determined by responsesof POAH thermosensitiveneuronsand to be regulated by both circadianand homeostaticprocesses.Many known chemomodulators of SWS appear to act on this hypnogenic thermoregulatory system. At a functional level, SWS-inducedbrain and body cooling would provide several adaptations including lower energy utilization, reduced cerebra/metabolism, protection of the brain against the sustainedhigh temperaturesof wakefulness, facilitation of immune defenseprocessesand regulation of the timing of behavioral activity relative to the circadian light-dark cycle. This concept provides a comprehensivemode/for analysis of sleep homeostasis.

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Fig. 1. A schematic summary of the integration of thermoregulatory mechanisms in the preoptic-anterior hypothalamic (POAH) area with neural networks regulating sleep, depicted in a sagittal view of the cat brain. (A) We hypothesize that warm-sensitive neurons, which increase their discharge in response to brain temperature, facilitate hypnogenic activity in conjunction with other heat loss processes. As a result of the loss of warm sensitivity after lesions ('1 '), compared to control levels ('2'), higher brain temperatures are required to induce sleep onset. Dynamic changes in warm sensitivity could account for circadian patterns in sleep propensity and responses to sleep factors. As expected in our model, changes in warm sensitivity from '1' to '2' were observed in SWS, compared to wakefulness. (B) The hypnogenic output from the POAH may be conveyed by neurons in the adjacent basal forebrain (BF). A subgroup of neurons in this area exhibit selectively increased in SWS. These neurons begin to increase their firing rates 10-15 s before the initial sleep spindle of a sleep episode (vertical dashed fine), supporting the hypothesis that they may help induce SWS. (From Ref. 26.) Sleep-active basal forebrain neurons may be activated during wakefulness by warming the POAH. (C) Data used for analysis of connectivity of basal forebrain neurons. Vertical arrows indicate timing of electrical stimulus pulses to possible projection sites of neurons. Antidromic activation is shown by fixed latency responses to high frequency paired pulses (upper trace) and the collision of the antidromic spike with a spontaneous spike (lower trace). Both sleep-active and waking-active basal forebrain neurons exhibited direct projections to neocortex and the midbrain reticular formation, but sleep-active neurons could be differentiated on the basis of lower conduction velocities. (From Ref. 25. Horizontal bar = I ms.) (D) Peristimulus time histogram of neuron recorded in the midbrain reticular formation (MRF), showing response to electrical pulse stimulation of lateral POAH. Stimulation of either medial or lateral POAH or basal forebrain produced MRF discharge suppression for 30-90 ms. Since the MRF may induce EEG and behavioral activation, discharge suppression may facilitate sleep onset. (The histogram is based on 100 stimuli. From Ref. 30.)

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including cutaneous vasodilation, sweating, or panting, depending on ambient temperature 8. In kangaroo rats, Glotzbach and Heller~4 assessed the regulated temperature during sleep and wakefulness by measuring the threshold and rate of change of heat production induced by progressive local cooling of the thermoregulatory center in the preoptic area of the hypothalamus, using a waterperfused thermode. They found a decrease in the slope of the metabolic response to hypothalamic cooling during SWS as compared with wakefulness. This finding indicated that the SWS-evoked decrease in body temperature is controlled by changes in the sensitivity of hypothalamic thermoregulatory mechanisms. Other studies demonstrate that increased SWS can also be a response to thermal stimuli. First, raising brain and body temperature during wakefulness was recently shown to be one of the few TINS, Vol. 13, No. 12, 1990

experimental manipulations, in addition to sleep deprivation, that increases subsequent SWS in humans. Home and Reidis and Bunnell et al. ~6 confirmed earlier reports that elevations of body temperature achieved by having subjects sit in a hot bath for 60-90 minutes, increased the duration of stages 3-4 sleep that night. Increases in stages 3-4 sleep can be considered to reflect increases in the intensity or depth of sleep. In addition, Home and Moore ~7 showed that the increased stage 3-4 sleep following some types of exercise was completely dependent upon body heating, and could be eliminated if body heating during exercise was prevented by cooling subjects with a fan. The observation that sleep is facilitated by waking heat loads argues for the hypothesis that cooling during sleep is more than one of the several physiological correlates of SWS. Rather, cooling during sleep would appear to be related to its homeostatic functions. 481

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In these experiments, body heating occurred in the afternoon; SWS was augmented several hours later, during nocturnal sleep. We consider the observation that the compensation for body heating when awake is delayed for several hours to be particularly intriguing. We were led to speculate that there is a mechanism which stores information about heat loads during wakefulness, a type of 'memory' to be expressed during subsequent sleep. The effect of such a memory would be to induce delayed compensation for heat loads while awake through sleep-related cooling, thereby providing long-term temperature regulation. Long-term temperature regulation involving sleep is also suggested by sleep deprivation studies (see below).

Hypothalamic mechanismsof sleep and thermoregulation A relationship between control of sleep and thermoregulation has also emerged from studies of brain mechanisms. The existence of a sleep controlling mechanism in the preoptic area-anterior hypothalamus (POAH) has been confirmed by many research groups. This is the only brain site where lesion, stimulation, and neuronal recording methods all provide evidence for a hypnogenic function 3. In addition, the POAH is a site of critical thermoregulatory mechanisms in mammals, and contains a high concentration of strongly warm-sensitive and coldsensitive neurons that can control both autonomic and behavioral thermoeffector activities. A stronger temperature sensitivity and a relationship to thermoeffector control distinguish POAH thermoregulatory neurons from more weakly thermoresponsive neurons found in some other brain sites. In several species, it has been demonstrated that local hypothalamic warming evokes immediate sleep onset (see Ref. 8). In addition, SWS can be increased over control levels for several hours by 'clamping' the POAH at an elevated temperature TM. These studies support the concept that the POAH has both acute sleep-inducing and tonic sleepregulating mechanisms that are integrated with thermoregulatory processes and that activation of warm-sensitive neurons induces SWS (Fig. 1A). We have now demonstrated a relationship between POAH hypnogenic and thermoregulatory processes in another way 3,19. Cats with neurotoxininduced medial POAH lesions exhibited sleep suppression when studied at 23°C, a non-stressful ambient temperature. This confirmed previous studies 3. In addition, the brain temperature threshold for induction of panting was elevated by 1.5-2.0°C, showing an abnormality in response to heat. When these 'insomniac' cats were then exposed to a higher ambient temperature of 33°C, brain temperature was elevated, but sleep was restored to prelesion levels. This elevated ambient temperature did not increase sleep in control animals. We interpret this study as showing that medial POAH neuronal loss produced a deficit in warmsensitivity resulting in an elevated temperature threshold for activation of two forms of heat loss, panting and sleep. We assume that our restricted 482

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medial POAH lesions spared some thermoregulatory neurons which could produce regulatory heat loss and sleep responses to a sufficiently strong thermal stimulus, as provided by a higher ambient temperature. The critical findings are that the POAH hypnogenic processes are coupled to thermoregulatory heat loss mechanisms and appear to be controlled in relation to a brain temperature threshold. Conditions which raise or lower this hypnogenic temperature threshold and cause sleep suppression or pathological sleepiness could include neuropathologies, endocrine states such as estrus, and effects of endogenous or exogenous neurochemical agents (see below). The thermoregulatory model of sleep predicts that medial POAH thermosensitive neurons will exhibit progressive changes in their thermosensitivity which would induce circadian and ultradian rhythms in sleep onset, heat loss during SWS, and satiation of sleep 'drive' resulting from sustained sleep. In particular, increased sleep propensity would result from a regulated increase in warm sensitivity or decreased cold sensitivity. The study of medial POAH thermosensitive neurons, which may mediate regulation of SWS, is in an early stage, but some supportive evidence is available. Experiments must be done in unanesthetized animals which can exhibit natural sleep and waking. Studies of POAH neurons have found that this site is unique among hypothalamic nuclei in having a large fraction of cells that increase discharge rate during SWS as compared to a wakeful state 2°. Such cells would be logical candidates for SWS-controlling neurons, although it will be necessary to show how such neurons are controlled by thermoregulatory mechanisms and how they are integrated with hypnogenic processes. Studies of identified POAH warm-sensitive and cold-sensitive neurons during wakefulness and sleep have been done by two research groups. Parmeggiani and associates21 have reported that a pooled population of warm-sensitive neurons in cats had slightly increased thermosensitivity during SWS compared to a wakeful state, as predicted by the model. In kangaroo rats, Glotzbach and Heller 22 found that five of 15 individually analysed warmsensitive neurons increased their thermosensitivity during SWS. Several cold-sensitive neurons showed lower thermosensitivity in SWS, a change that might also drive sleep-related reductions in body temperature. Thus, changes in POAH neuronal thermosensitivity, which are consistent with our hypothesis, have been documented (Fig. 1A). However, therrnosensitive neurons are heterogeneous with respect to chemosensitivity, afferent input, and, as noted above, interaction with sleep-waking state. It will be important to identify POAH neuronal subgroups that modulate sleep. We add that thermoregulatory mechanisms are not confined to the anterior hypothalamus, and that thermoregulatory neurons found in posterior hypothalamus, pons, medulla, and spinal cord may participate in the sleep-wake modulation also associated with the sites. We have made some progress in understanding TINS, Vo]. 13, No. 12, 1990

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how thermosensitive neurons of the medial POAH may modulate other brain sites involved in sleep. One site of interaction is the adjacent ventrolateral basal forebrain. This region, which includes the magnocellular lateral POAH and substantia innominata, contains sites where electrical stimulation may induce SWS and lesions may reduce sleep3,23. Using neuronal unit recording methods within this region, we identified a very unusual group of neurons, constituting about 24% of the sample, which increased discharge selectively during sleep onset and maintained elevated discharge tonically during SWS24. The remaining neurons were more active during waking and REM sleep like most neurons studied in other parts of the CNS. Of course, increased discharge during SWS does not prove a causal role in sleep control, but such an interpretation is consistent with the findings of stimulation and lesion studies of this site. A sample of these 'sleep-active' neurons was also found to increase discharge 10-15 s before the initial appearance of EEG synchrony during transitions from waking to sleep25 (Fig. 1 B). This property of anticipation of the waking-sleep transition is also consistent with the hypothesis that these neurons participate in the hypnogenic functions of this brain region. A recent study 26 showed how thermosensitive elements in the medial POAH may interact with sleep- and waking-active neurons in the lateral POAH and basal forebrain. Cats were prepared with thermodes in the medial POAH, and recording electrodes in the lateral POAH and adjacent basal forebrain. We observed that medial POAH warming during wakefulness could excite sleep-active neurons, and suppress discharge of waking-REM-active neurons in the lateral sites. Thermal stimulation was restricted to the medial POAH and did not directly affect recording sites. Therefore, thermosensitive neurons of the medial POAH may exert hypnogenic effects through synaptic actions in the adjacent basal forebrain. An additional study examined the efferents from both sleep-active and waking-active basal forebrain neurons using antidromic activation techniques in the unanesthetized animal 2s. Both types of neurons could be activated antidromically from pathways to neocortex (Fig. 1C) and to mid-brain reticular formation (MRF). However, it was possible to differentiate waking-active and sleep-active cell types on the basis of conduction velocity. Sleepactive neurons had more slowly conducting axons. Studies in anesthetized rats have also distinguished two magnocellular basal forebrain cell types on the basis of conduction velocity, and other differentiating properties. These two cell types may have different neurochemical properties, and can be hypothesized to correspond to the cholinergic and GABAergic neurons which occur in this region 27. The smaller GABAergic neurons would be expected to have the lower conduction velocities seen in the sleep-active neurons, although a definitive study is needed. The main conclusion is that sleep-active neurons constitute a discrete cell type with direct connections to neocortex and MRF. TINS, VoL 13, No. 12, 1990

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CSN Fig. 2. Hypothetical conception of how certain sleep factors may regulate SWS and body temperature. In one model, prostaglandins PGD2 and PGE2stimulate receptors on POAH hypnogenic warm-sensitive neurons (WSN) or coldsensitive neurons (CSN), respectively, to induce either SINS or waking. PGD2 synthetase is increased during the period of sleep in the rat 36. Since a heat load during wakefulness may increase subsequent SWS, we may hypothesize that this facilitates production of PGD2 synthetase. In another model, IL-1 has two effects: induction of fever through induction of prostaglandin synthesis from arachidonic acid (AA), and direct action on hypnogenic neurons. These two effects can be separated through pharmacological pretreatment42. Other sleep factors may modulate sleep through similar actions (see text). Within the MRF is the classical EEG and behavioral activating mechanism discovered by Moruzzi and Magoun 28. Neurons in the MRF may show tonically increased discharge during a wakeful state 29. To clarify the significance of the pathway from the basal forebrain to the MRF, we recorded neuronal unit discharge in the MRF, and analysed the effects on discharge produced by single electrical pulse stimulation of both medial POAH and more lateral basal forebrain sites. Stimulation at either site during waking produced MRF discharge suppression for 30 to 90 ms, sometimes preceded by brief excitation 3° (see peristimulus histograms, Fig. 1 D). Warming the medial POAH can also inhibit MRF discharge 31, and electrical stimulation of this site will suppress ongoing behavior 32. Thus, sustained medial POAH or BF discharge, induced by thermosensitive mechanisms, would inhibit the MRF arousal system, potentially facilitating sleep onset in this way. The reticular activating system extends rostrally into the posterior hypothalamus. In the latter site, induction of neuronal blockade by microinjection of muscimol, antagonized the sleep suppression following POAH lesions33. This result suggests that posterior hypothalamic EEG activating neurons are disinhibited after POAH lesions, facilitating arousal. Therefore, we predict that POAH and BF stimulation would suppress neuronal discharge within the posterior hypothalamus as in the MRF. The POAH and sleep chemomodulation Recent progress has also been made in the understanding of the role of the POAH in the neurochemical control of SWS. Microinjections of the benzodiazepine hypnotic, triazolam 34, the putative sleep factor muramyl peptide from human urine 35 and a prostaglandin, PGD2 (Ref. 36), the serotonin precursor, 5-HTP (Ref. 37), or adenosine 38 were all found to trigger or increase SWS. In each case, the POAH or adjacent hypothalamic sites were responsive to chemo-induction of SWS, while extrahypothalamic forebrain or lower brainstem sites were usually unresponsive. These 483

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studies show the critical importance of the POAH and adjacent regions in the chemomodulation of SWS. One well-developed model is that described in a series of studies by Hayaishi and co-workers (see Ref. 36) (Fig. 2.). POAH microinjection of PGD2 increased SWS in rats and monkeys 39, and microinjection of another prostaglandin, PGE2, promoted waking. PGD2 receptors are localized in the POAH, and PGD2 has been shown to modulate POAH neuronal thermosensitivity directly. A tonic sleeprelated role is suggested by the finding that PGD2 synthetase activity was increased during the diurnal period (light) of increased sleep in the rat, but the activity of the degrading enzyme was unchanged. Prostaglandin synthesis inhibitors (Declofenac, indomethacin, salicylic acid - aspirin) decrease SWS4°. It might be possible that PGD2 accumulation, or a receptor-mediated consequence of PGD2 binding could account for the 'memory' for prior heat exposure. Horne 41 recently showed that aspirin decreased waking body temperature in nonfebrile men, and argued that this temperature decrease could account for the reduction in SWS that followed the administration of aspirin. Other putative sleep factors, including muramyl peptides, cytokines such as interleukin 1 (IL-1), and growth hormone-releasing factor, also modulate thermoregulation and could regulate SWS through mechanisms similar to that of PGD2 (Refs 42, 43). Some recently described sleep factors are also pyrogenic. However, for some agents such as IL-1, a pyrogenic action can be blocked by pharmacological pretreatment without affecting the hypnogenic response. Thus, there must be at least two receptor mechanisms, one inducing fever, another inducing sleep and heat loss (Fig. 2). The effects of sleep factors could be mediated either by pyrogenic action, that is, elevation of brain temperature above the hypnogenic threshold, leading to direct activation of hypnogenic warm-sensitive neurons, or by increasing warm sensitivity of hypnogenic neurons, which would induce sleep and heat loss rather than fever. Some agents may stimulate both types of receptor mechanisms, perhaps depending on agonist concentration. We believe that the observation that both hypnogenic and thermoregulatory actions are common to a wide range of agents provides general support for the concept of thermoregulatory control of SWS. The exact cellular mechanisms underlying the interactions of hypnogenic and thermoregulatory effects of these agents within the POAH are important problems for future study.

Circadian features of human sleep patterns Findings from the circadian analysis of human sleep are also compatible with our model. It has been shown that a circadian body temperature rhythm strongly modulates sleep. Within a 24-hour day, a biphasic sleep propensity was found in human subjects studied in time-cue free environments (temporal isolation), or using the method of periodic nap opportunities 44,45. While one peak corresponds to the usual nocturnal sleep period near the time of the trough of circadian temperature 484

rhythm, a second peak occurs at the time of the afternoon temperature peak. This has been interpreted as contradicting any homeostatic model of sleep, since sleepiness actually declines during the early evening, even as duration of prior waking increases. However, a thermoregulatory control model can explain this finding. Afternoon sleepiness may be driven directly by the body temperature elevation at the circadian peak, which may reach the hypothesized hypnogenic temperature threshold at this time. The evening decline in sleepiness would reflect the coincident decrease in temperature, a manifestation of the evening circadian 'downregulation' of temperature 46. Decreased brain temperature would, in turn, decrease activity of sleep-inducing warm-sensing neurons. Later in the evening, the accumulated effects of high awake temperatures on hypnogenic processes, as described above, in combination with circadian changes in hypnogenic thresholds, sleep posture and environmental light-dark rhythms are hypothesized to increase again the output of thermosensitive neurons to induce sleepiness. The predictions of a formal thermoregulatory model of human sleep patterns still need to be evaluated, but already we may conclude that the principal features of human sleep patterns and sleep propensity are predicted by the circadian temperature rhythm, and are consistent with thermoregulatory control of SWS.

Functional aspects of sleep and brain cooling States that are readily recognized as SWS and REM sleep states are found in both birds and mammals, and are different from states of sleep-like rest in poikilothermic vertebrates. The latter are not associated with slow-wave EEG activity. Transitions between rest and active states occur slowly in poikilotherms and are dependent on ambient conditions. The rest-activity patterns of poikilotherms are evolutionary precursors of sleep states in homeotherms, but seem to be regulated more by environmental temperature rather than intrinsic mechanisms1. Thus, a functional relationship is suggested between evolution of homeostatic sleep and endothermic thermoregulation in mammals and birds. A thermoregulatory model of SWS can be integrated with several approaches that have been taken to the issue of sleep function in homeotherms (Table I). First, it has been proposed that sleep functions to conserve energy by reduction of metabolic rate5 or simply through enforcement of inactivity 47. The higher basal metabolism of homeotherms increases the adaptive value of energy conservation. Through energy conservation, survival would be extended under conditions of limited food supply. Support for such a model includes the observations that the energy-conserving hypometabolic states of hibernation and shallow torpor are contiguous with SWS. Increases in SWS observed during food restriction in certain species are also consistent with such a model s. Although based on different concepts, the energy conservation model depends mechanistically upon a coordinated increase in SWS and a lowering TINS, VoL 13, No. 12, 1990

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of the regulated body temperature. We may hypothesize that chemical signals related to energy balance would modulate the sensitivity of hypnogenic warm-sensitive neurons in order to provide the observed sleep and thermoregulatory responses. Many animals seek insulated nests and postures during sleep. This is one way in which the degree of body temperature decrement during SWS is limited, even as metabolic heat production falls. Thus, energy conservation, sleep regulation, behavior, and thermoregulation must be integrated processes. Some investigators have proposed a relationship between SWS and high waking cerebral metabolism, suggesting that sleep provides 'rest' for certain cerebral processes48. While many effects of sleep deprivation result from sleepiness or motivational factors, extended sleep deprivation in humans seems to produce cognitive deficits that cannot be explained by these factors. Thus, longlasting cerebral activity may lead to cerebral 'fatigue'. While the nature of cerebral fatigue is unknown, a lowering of cerebral metabolism in conjunction with SWS reverses the fatigue. Thus, down-regulation of cerebral temperature and metabolism could be the mechanism required for restoration of mechanisms that exhibit fatigue during extended wakefulness. Of course, cerebral temperature and metabolic rate have a complex relationship (depending also on cerebral heat loss), but would certainly be correlated under many conditions. Sleep functions have also been explored by determining the detrimental effects of sleep deprivation. Rechtschaffen and colleagues2,49.s° have recently shown that sustained sleep deprivation in rats leads to death in 2-3 weeks, confirming earlier anecdotal observations. In these experiments, computerized detection of EEG sleep activates a rotating disk which could push the rats into shallow water unless they awaken. At the onset of the procedure, sleep-deprived rats exhibited a striking change in heat retention; they lost heat rapidly, but compensated by dramatically increasing food intake and metabolic rate. Initially, sleep-deprived rats had slightly higher mean temperatures than yoked controls, possibly reflecting the absence of sleepassociated cooling. After about two weeks, deprived rats exhibited sustained hypothermia, reduced EEG amplitude, and rapid death. This research group has studied and excluded some possible mechanisms of physiological failure (e.g. immune disorder, organ pathology, weight loss). While this is a complex experiment, and many questions remain, thermoregulatory or metabolic disorders appear to be critical effects of sleep deprivation. Several studies have shown that sleep-deprived humans also exhibit lower daytime body temperatures than controls (e.g. Ref. 51). These findings suggest that the elevated waking temperatures in homeotherms cannot be sustained without periodic cooling during sleep, and that, in the absence of sleep, regulated cooling occurs during waking. A long-term thermoregulatory role for sleep is an obvious interpretation of these results. TINS, Vol. 13, No. 12, 1990

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Table I. Possiblefunctional effects of thermoregulatory control of slow-wave

sleep (1) Energyconservation (2) Reducedcerebralmetabolism to restorecertainfatiguable cerebral processes (3) Regulationof meantemperaturebelow waking levelsto avoid biophysical disorders resultingfrom sustainedhigh waking temperatures (4) Facilitationof immune response (5) Circadiancontrol of behavioral activation relatedto ecological niche We have proposed an additional functional benefit effect of SWS-related brain cooling which could explain the down-regulation of temperature during sleep deprivation. This hypothesis is based on the concept that mammals and birds have evolved to maintain high waking brain temperatures, close to the levels of potential functional or physical disorder. There are potential selective pressures that might have led to evolution of waking temperatures that approach damaging levels. Maximal psychomotor s2 and aerobic53 performance are associated with peaks in the circadian temperature rhythm, and subjective alertness is positively correlated with temperature across the circadian cycle54. The cool human brain is experienced as 'groggy'. In order to be alert, our brains must be warm (but not too warm). It has also been established that the high basal metabolism of homeotherms is associated with aerobic stamina to sustain locomotor activity, extend territorial range for food acquisition, and for chase or escape from predators. Poikilotherms may have equal initial running speed, but fatigue quickly. Indeed, increased stamina has been suggested as the principal basis underlying the initial evolution of homeothermy s3. The competitive advantages and probable selective pressures associated with high brain and body temperatures may have led homeothermic species to evolve the highest temperatures compatible with biochemical stability in each species. Yet the brain is sensitive to hyperthermia, and a brain temperature only slightly above normal is associated with disorder of mental status. Loss of consciousness is the initial effect of heat stroke, which usually causes irreversible neuropathology5s. Sleep deprivation is thought to increase susceptibility to heat stroke 5~. Thus, it is plausible to speculate that avian and mammalian brain temperatures while awake are normally regulated at levels that cannot be sustained for days without biophysical dysfunction, and that even the modest daily cooling during sleep may have critical benefits. The detrimental effects of sleep deprivation are characterized by a long-term cumulative course56. We hypothesize that detrimental changes in brain mechanisms that are sensitive to high temperatures would follow a similar course. A functional role for sleep in immune mechanisms has been proposed by Krueger and collagues43 as a result of the observation that many immune factors also promote SWS. These include muramyl peptides, lipid A, IL-1, tumor necrosis factor, and interferono~2.These agents are also pyrogenic and may act on POAH sites. The pyrogenic and somnogenic effects 485

10 Jouvet, M., Buda, C., Debilly, G., Dittmar, A. and Sastre,J-P. (1988) CR Acad. Sci. Paris 306, 69-73 11 Gillberg, M. and Akerstedt, T. (1982) Sleep 5,378-388 12 Barrett, J., Morris, M. and Lack, L. (1987) Sleep Res. 16, 596 13 Kolvalzon, V. M. and Mukhametov, L. M. (1982) J. EvoL Biochem. PhysioL 18, 307-309 14 Glotzbach, S. F. and Heller, H. C. (1976) Science 194, 537-539 15 Home, J. A. and Reid, A. J. (1985) Electroencephalogr. C/in. NeurophysioL 60, 154-157 16 Bunnell, D. E., Agnew, J. A., Horvath, S. M., Jopson, L. and Wills, M. (1988) Sleep 11,210-219 17 Home, J. A. and Moore, V. J. (1985) Electroencephalogr. Cfin. Neurophysiol. 60, 33-38 18 Sakaguchi,S., Glotzbach, S. F. and Heller, H. C. (1979)Am. J. Physiol. 237, R80-R88 19 Szymusiak, R., Danowski, J. and McGinty, D. (1989) Sleep Res. 18, 24 20 Findlay, A. R. and Hayward, J. N. (1969) J. PhysioL 201, 237-258 21 Parmeggiani, P. L., Cevolani, D., Azzaroni, A. and Ferrari, G. (1987) Brain Res. 45, 79-89 22 Glotzbach, S. F. and Heller, C. H. (1984) Brain Res. 309, 17-26 23 Szymusiak, R. and McGinty, D. (1986) Exp. NeuroL 94, 598-614 24 Szymusiak, R. and McGinty, D. (1986) Brain Res. 370, 82-92 25 Szymusiak, R. and McGinty, D. (1989) Brain Res. Bull. 22, 423-430 26 Szymusiak, R. and McGinty. D. in The Diencephalon and Sleep (Mancia, M. and Marini, G., eds) (in press) 27 Fisher, R. S., Buchwald, N. A., Hull, C. D. and Levine, M. S. (1988) J. Comp. NeuroL 272, 489-502 28 Moruzzi, G. and Magoun, H. W. (1949) Electroencephalogr. Clin. Neurophysiol. 1,455-473 29 Steriade, M., Oakson, G. and Ropert, N. (1982) Exp. Brain Res. 46, 37-51 30 Szymusiak, R. and McGinty, D. (1989) Brain Res. 498, 355-359 31 De Armond, S. J. and Fuso, M. M. (1971) Exp. NeuroL 33, 653-670 32 Sterman, M. B. and Fairchild, M. D. (1966) Brain Res. 2, 205-217 33 Sallanon, M., Denoyer, M., Kitahama, K, Aubert, C., Gay, N. and Jouvet, M. (1989) Neuroscience 32, 669-683 34 Mendelson, W. B., Martin, J. V., Perlis, M. and Wagner, R. (1989) Neuropsychopharmacology 2, 61-66 35 Garcia-Arraras, J. E. and Pappenheimer, J. R. (1983) J. Neurophysiol. 49, 528-533 36 Hayaishi, O. (1988) J. Biol. Chem. 263, 14593-14596 37 Denoyer, M., Sallanon, M., Kitahama, K., Aubert, C. and Jouvet, M. (1989) Neuroscience 28, 83-94 38 Ticho, S. R. and Radulovacki, M. (1989) Soc. Neurosci. Abstr. 15, 242 39 Ueno, R., Ishikawa, Y., Nakayama, T. and Hayaishi, O. (1982) Biochem. Biophys. Res. Comm. 109, 576-582 Selected references 40 Naito, K., Osama, H., Ueno, R., Hayaishi, O., Honda, K. and Inoue, S. (1988) Brain Res. 453, 329-336 1 McGinty, D. J. and Siegel, J. M. (1983) in Handbook of Behavioral Neurobiology (Vol. 6: Motivation) (Satinoff, E. 41 Home, J. A. (1989) Sleep 12, 516-521 and Teitelbaum, P., eds), pp. 105-181, Plenum Press 42 Krueger, J. M., Walter, J., Dinarello, C. A., Wolff, S. M. and 2 Rechtschaffen, A., Gilliland, M. A., Bergmann, B. M. and Chedid, L. (1984) Am. J. PhysioL 246, R994-R999 Winter, J. B. (1983) Science 221, 182-184 43 Krueger, J. M., Obal, F. Jr, Johanssen, L., Cady, A. B. and 3 McGinty, D. and Szymusiak, R. (1989) in Slow Wave Sleep: Toth, L. (1989) in Slow Wave Sleep: Physiological, PathoPhysiological, Pathophysiological and Functional Aspects physiological and Functional Aspects (Wauguier, A., Dugovic, (Wauquier, A., Dugovic C. and Radulovacki, M., eds), pp. C. and Radulovacki, M., eds), pp. 75-90, Raven Press 61-74, Raven Press 44 Zulley, J., Wever, R. and Aschoff, J. (1981) Pfl(~gers Arch. 391,314-318 4 Heller, H. C., Glotzbach, S., Grahn, D. and Radeke,C. (1988) in Clinical Physiology of Sleep (Lydic, R. and Biebuyck, J. F., 45 Richardson,G. S., Carskadon, M. A., Orav, E. J, and Dement, eds), pp. 145-158, American Physiological Society W. C. (1982) Sleep 5, $82-$94 5 Berger, R. J. and Phillips, N. H. (1988) Acta PhysioL Scand. 46 Stephenson, L. A., Wenger, C. B., O'Donovan, B. H. and 133, 21-27 Nadel, E. R. (1984) Am. J. PhysioL 246, R321-R324 6 Szymusiak, R. and Satinoff, E. (1985)in Brain Mechanisms of 47 Allison, T. and Van Twyver, H. (1970) Nat. Hist. 79, 56-65 Sleep (McGinty, D., Drucker-Colin, R., Morrison, A. and 48 Home, J. (1988) Why We Sleep, Oxford University Press Parmeggiani, P. L., eds), pp. 301-319, Raven Press 49 Bergmann, B. M., Everson, C. A. and Kushida, C. A. (1989) Sleep 12, 31-41 7 Sewitch, D. E. (1987) Psychophysiology 24, 200-215 80bal, F. Jr (1984) Exp. Brain Res. 5uppL 8, 157-172 50 Benca, R. M., Kushida, C. A., Everson, C. A., Kalski, R., 9 Parmeggiani, P. L. (1980) in Physiology in Sleep (Orem, J. Bergmann, B. and Rechtschaffen,A. (1989) Sleep 12, 57-52 and Barnes, C. D., eds), pp. 97-143, Academic Press 51 Froberg, J. E. (1977) Biol. PsychoL 5, 119-134

of these agents can be separated by pharmacological treatments 42 and could be mediated by different mechanisms (see above). However, SWS can be enhanced during the plateau phase of a fever 57. There may be additive effects of sleep and fever in support of immune defense mechanisms. As noted above, behavioral activation is stimulated by increasing body and brain temperature. Therefore, circadian temperature rhythms that modulate sleep and wakefulness also control the timing of behavioral activity relative to the light-dark cycle. In this way, circadian temperature rhythms determine the circadian aspect of ecological niche of a species, producing wakefulness at a time that maximizes the efficiency of food seeking, social and territorial adaptation, and minimizes predation. The POAH is a major target of efferents from the adjacent suprachiasmatic nucleus, the site of the circadian clock in mammals 58. However, while circadian control of behavioral timing is clearly important, we doubt that sleep occurs only to control the timing of behavior. An exclusively behavioral rhythm theory of sleep-wake control does not account for the thermoregulatory and cognitive effects of sleep loss noted above. It is possible that a complex process like sleep could serve each of the functions suggested in Table I, with the functions having somewhat different importance in different species. Our hypothesis emphasizes the common link in these functions, which is control by thermoregulatory mechanisms. Subtle differentiation of receptor mechanisms on hypnogenic thermoregulatory neurons within the POAH could integrate a number of functional requirements, including avoidance of sustained heat loads, reduced cerebral metabolism, energy conservation, circadian timing of behavior, and enhanced immune function. A thermoregulatory control hypothesis provides a basis for experimental analysis of functional aspects of the homeostatic regulation of sleep, and for understanding observations of increasing sleep after waking heat loads, waking hypothermia after sleep deprivation, and the close coupling between circadian rhythms in sleep and body temperature.

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52 Aschoff, J., Giedke, H., Poppel, E. and Wever, R. (1972) in Space Environ. Meal. 47, 280-301 Aspects of Human Efficiency (Colquhoun, W. P., ed.), pp. 56 Carskadon,M. A. and Dement, W. (1981) Psychophysiology 135-150, The English UniversitiesPress 18, 107-113 53 Bennett,A. F. and Ruben,J. A. (1979) Science206, 649-653 57 Kent,S., Price,M. and Satinoff, E. (1988) PhysioL Behav. 44, 54 Czeiler, C. A., Weitzman, E. D., Moore-Ede, M. C, and 709-715 Zimmerman, J. C. (1980) Science 210, 1264-1267 58 Meijer, J. H. and Rietveld, W. J. (1989) PhysioL Rev. 69, 671-707 55 Shibolet, S., Lancaster, M. C. and Danon, Y. (1976) Aviat.

Is the cerebral cortex modular? N. V. Swindale Two types of modular subunit, differing in size, have been hypothesized to exist in the cerebra/cortex. The first, known as a minicolumn, consists of a group of 110 +_ 10 cells which form a fascicle about 30 #m in diameter oriented perpendicular to the cortical surface. Mini-columns are believed to be organized into larger modular groupings, referred to here as macro-columns, with a diameter of about a millimetre or less. Nicholas Swindale argues in this article that there is very little real evidence in favour of eithertype of module. As an alternative, he suggeststhat the diversity of types of columnar organization, both within and between different cortical areas, may reflect the diversity of types of information stored in the cortex. Consequently,columnar organization can be expected to vary within and between species, and even between different individuals of the same species. This new interpretation is in line with current neural network theories, which do not demand the existence of structural modularity, but show how complex forms of organization can result from the existence of simple processing rules between the elements of a structure given complex structured inputs.

similar internal structure and surprisingly little variation of diameter (200-300 l~m)'. Eccles3 gives a similar definition, although according to Mountcastle 1 the larger unit (i.e. the macro-column) has a diameter of 500-1000 I~m.

Mini-columns Several observations have led to the idea that mini-columns are a basic structural and functional subunit of the cortex. Nissl stains of sections cut perpendicular to the surface of the cortex show that neuronal cell bodies are aggregated into chains or cords, separated by neuropile. These chains are about 30-50 t~m apart, and give the appearance of running continuously from white matter to the pial surface. Counts of cell numbers in columns of cortical tissue about 30 ~m in diameter and extending from white matter to pia4 give remarkably constant values of 110 + 10 cells in many different The idea that the cerebral cortex is a mosaic of cortical areas and species, except in primate visual modular subunits, each similar in size and structure cortex where the number is about 270. Physiological and containing a relatively small number of neurons, studies 1,5 show that cells in the same column of is obviously appealing. The process of trying to tissue, and thus cells in the same mini-column, tend understand how the cortex works would be greatly to have similar response properties, e.g. preferred simplified, because any finding made about the orientation in the visual cortex or receptor modality function of one module could be generalized to the in the somatosensory cortex. whole cortex. Examples of repetitive structural However, the evidence for mini-columns is not groupings in other neural structures are not uncom- easy to interpret. The origin of the vertical striations mon, and occur for example in the optic lobe of the seen in Nissl-stained tissue is unclear, and it is fly and in the cerebellum. It seems natural to suspect difficult to determine whether they define single that the mammalian cerebral cortex might have a groups of cells extending from white matter to pia. similar repetitive, or modular, construction, and The phenomenon of dendritic bundling (see some eminent neuroscientists, notably Mountcastle ~, Feldman 6, for review) in which groups of apical Szent&gothai 2 and Eccles3, have proposed that this dendrites run in close proximity from cell body to is so. layer I of the cortex might be related to this. Tissue In fact, not one but two kinds of modular subunit sections cut parallel to the cortical surface show that have been hypothesized to exist. The first, known as the bundles have a spacing of about 30-50 I~m, a mini-column, is defined by Mountcastle ~ as 'the which is similar to mini-column spacing, and since basic modular unit of the neocortex.., it is a the bundles exclude cell bodies it may be this that vertically oriented cord of cells formed by the causes cell bodies to be grouped in apparently migration of neurons.., it contains about 110 vertical configurations. The bundles themselves cells... (and)... occupies a gently curving, nearly might contain dendrites from cells in different minivertical cylinder of cortical space with a diameter of columns, and it might legitimately be supposed that about 30 ~m'. The second kind of module consists this method of grouping cells would be as valid as of an aggregation of a few hundred mini-columns the groupings revealed by cell body staining. forming a larger processing unit, which it is useful to Evidence based on the constancy of cell number refer to as a macro-column. Thus, according to within mini-columns is similarly difficult to interpret. Szent~gothai 2 'the cerebral cortex has to be envis- Although the variation in cell numbers measured by aged as a mosaic of columnar units of remarkably Rockel et al. 4 was strikingly small, a subsequent TINS, Vol. 13, No. 12, 1990

© 199o,ElsevieSci r encePublishersLtd.(UK) 0166-2236/90/$02.00

N. V. Swindaleis at the Departmentof Ophthalmology, 2550 WillowStreet, Universityof British Columbia, Vancouver,BC, VSZ2Ng, Canada.

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