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Sleep and Aging PDF

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TABLE OF CONTENTS Preface vii Chapter 1 Evolutionary Aspects of Sleep and Its REM and NREM States . . . . . . . . . . . . 1 J. Lee Kavanau Chapter 2 Sleep Disturbances in Aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Marci M. Loiselle, Melanie K. Means, and Jack D. Edinger Chapter 3 Sleep and Learning in Animal Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Barry W. Row and David Gozal Chapter 4 Sleep Disordered Breathing in the Geriatric Patient Population . . . . . . . . . . . . 79 Alon Y. Avidan Chapter 5 Sleep Associated Endocrine and Immune Changes in the Elderly. . . . . . . . . . . . 113 Boris Perras and Jan Born Chapter 6 Neurotrophic Factors and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Mark P. Mattson Chapter 7 Sleep and Aging: Molecular Approaches within a Systems Neurobiology Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Akira Terao and Thomas S. Kilduff List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 v PREFACE Abnormalities in sleep can be symptoms or causes of a variety of disorders, many ofwhichareassociatedwithagingandage-relateddisease.Forexample,insomniais a major component of clinical depression and anxiety disorders, and neurodegen- erative disorders such as Alzheimer’s and Parkinson’s diseases. Another sleep disorderofconsiderableconcernisapneawhichmayleadtobraindamageandeven sudden death. Sleep disorders in the elderly may involve changes in neural circuits thatregulatedifferentstatesofsleepincludingrapideyemovement(REM)andslow wave sleep (SWS), and circadian rhythms. The neurochemical basis of sleep disorders is beginning to be understood and this information is being used to develop new ways of preventing and treating sleep disorders. In this volume of Advancesin Cell Aging and Gerontologyentitled Sleep and Aging, expertsin brain aging and sleep, review key aspects of this complex and very important topic. The first chapter, written by J. Lee Kavanau, provides a fascinating account of evolutionary aspects of sleep and its different states. Questions such as why is sleep necessary for the survival of mammals and what is the role of sleep in memory, are considered. Marci Loiselle and her colleagues then provide a review of sleep disturbancesinaging includinghowsleep patternsarealteredinaging, thedifferent types of sleep disorders, and the evaluation and treatment of these disorders. Abnormalitiesinbreathingpatterns,suchassleepapnea,arecommonintheelderly. AlonAvidanreviewsthecharacteristicsandcausesofsleepdisorderedbreathingand current approaches for the medical management of these disorders. Considerable evidence is consistent with important roles for sleep in learning and memory. Barry Row and David Gozal provide a timely review of the results of studies in animals that reveal the effects of sleep on neural systems involved in synaptic plasticity and memory, and the cellular and molecular mechanisms by which sleep affects these processes.Theendocrine andimmunesystems arealteredduring aging inwaysthat reduce one’s resistance to stress, infections, and other environmental factors. Boris Perras and Jan Born describe how endocrine and immune functions change during sleep and wakefulness, and how the normal sleep-related fluctuations are affected by aging. Finally, I review emerging evidence that suggests important roles for neurotrophic factors in sleep and disorders of aging that involve abnormalities in sleep. By virtue of its roles in learning and memory, neurogenesis, depression and neurodegenerative disorders, brain-derived neurotrophic factor appears to be a particularly important neurotrophic factor in sleep regulation. Advances are being made in the understanding of the molecular and cellular biology of sleep, the roles of aging and disease in sleep disturbances, and how diseases of aging cause or exacerbate disorders such as insomnia and sleep apnea. This volume of ACAG will provide graduate students, postdoctoral fellows, and senior investigators in the field of sleep research with a valuable source of vii viii Preface informationthatwillbenefittheirresearch.Inaddition,neuroscientists,neurologists, and psychiatrists will learn that many of the neuronal circuits and neurochemicals that are altered in age-related neurodegenerative and psychiatric disorders are the sameasthoseinvolvedinsleepdisorders.Indeed,emergingfindingsfrompreclinical and clinical studies suggest that treatments beneficial for depression (serotonin reuptake inhibitors, for example) may also be effective for treating insomnia and neurodegenerative disorders. Sleep well and you will age gracefully. MARK P. MATTSON, PhD Advances in Cell Aging and Gerontology Evolutionary aspects of sleep and its REM and NREM states J. Lee Kavanau DepartmentofOrganismicBiology,EcologyandEvolutionUniversityofCalifornia,LosAngeles, CA90095-1606,USA.Tel:þ1-310-825-3474;fax:þ1-310-206-3987. E-mailaddress:[email protected] Contents 1. Introduction 2. Evolutionary origin of sleep 2.1. Schwartz’s admonition andRauschecker’s ‘‘Fundamental Dogma’’ 2.2. Restfulwaking, detailed focal vision, andconflicting brainactivities 2.3. Primitive sleepobviatedpotentially conflicting brainactivities 2.4. Vertebrates thatnever sleep 2.5. Need forsleepin congenitally andadventitiously blindmammals 2.6. Earliest sleep 2.7. Complex retinal processing 3. Warm-bloodedness and selectivepressures forREM andNREM sleep 3.1. Historical 3.2. Sleep wasnon-uniform beforethe origin of REMand NREMstates 3.3. Presence and absence ofthermoregulation duringsleep states 3.4. Implications for the evolutionof sleepstates 3.5. Influencesof ambienttemperature 3.6. Actions of brainwavesduring waking 3.7. Actions of brainwavesduring sleep 3.8. Long-term memorymaintenance 3.9. Basiclinks betweenmuscle-controlling andvisual circuits 3.10. Absence orlesser amountsof REMsleepin marinemammals and birds 3.11. Origin offast wavesof REMsleep 4. Evolutionary origin of sleep– withina brain-wave paradigm 5. Sequential cyclingof NREMand REMsleep 6. Overview AdvancesinCellAgingandGerontology,vol.17, 1–32 (cid:1)2005ElsevierB.V.AllRightsReserved. DOI:10.1016/S1566-3124(05)17001-1 2 J.L.Kavanau 1. Introduction Darwin’s discoveries in the field of evolution did much more than open our eyes to long-term influences of the environment on higher plants and animals. They led to enormously fruitful reorientations of studies in all fields of biology. Viewing biological phenomena from an evolutionary perspective frequently yields insights beyond those that can otherwise be discerned. However, paraphrasing Damasio’s (1999) remark: one could almost say that, until the last decade, neuroscience and cognitivesciencehaveproceededasifDarwinneverexisted.Inthischapter,Iemploy a Darwinian approach to the origin and functions of sleep and sleep states. Studies with the goal of identifying selective pressures that might have given rise to sleep and its rapid-eye-movement (REM) and non-rapid-eye-movement (NREM)states,couldcastlightontheirfunctions.Beingmostlymedicallyoriented, current studies of sleep have somewhat different objectives. Attention is directed primarily to mechanisms, for example, influences of various brain secretions on vigilance states. While significant medical progress, with great practical benefits, has been made along these lines, implications of the underlying mechanisms for sleep’s functions have been tenuous or non-existent. Further, one must distinguish between the functions of sleep and the activities that occur during sleep, and their benefits. Sometimes, the functions have been equated with the activities and benefits. Some treatments included evolutionary considerations, but they infrequently probedunderlyingselectivepressures.Almostallattentionhasbeendirectedtoward comparative aspects, such as the degrees to which sleep and its REM and NREM states occur in various species, and how they correlate with brain structures, anatomy, behavior, and ecology. These analyses inevitably lean heavily on information gleaned from evolutionary ‘‘endpoints,’’ perhaps millions of years removed from the selective pressures of origin, and often arrived at along different routes. Taken at face value, these endpoints can be misleading. Even before probing for the basic or primitive function(s) of sleep, the evolutionist anticipates that it will be expressible in terms of maintenance of an overall high efficiency of brain operation. No one would doubt that normal waking brains operate at high levels of efficiency, with responses to threatening circumstances having the highest priority. Accordingly, the provision of a suitably modified alternative vigilance state – sleep – in some animals, very likely functions to maintain brain operations at overall high levels of efficiency, by subsuming non-urgent activities that cannot be accomplished efficiently during a continuous waking state. 2. Evolutionary origin of sleep 2.1. Schwartz’s admonition and Rauschecker’s ‘‘Fundamental Dogma’’ In addressing the basic function of sleep – referred to by some as the ‘‘supreme mystery’’–namely,thefunctionthatprovidedtheevolutionaryselectivepressurefor EvolutionaryAspectsofSleepandItsREMandNREMStates 3 sleep’s origin, it is essential to heed Schwartz’s (1997) admonition to sleep researchers. Certain phenomena that characterize a given state, ‘‘...may mirror aspects of the mechanism for generating the state and its attendant phenomenology ratherthanthefunctionofthestate’’(originalitalics).Thiscautionishighlyrelevant for sleep studies, because some researchers assume that a sufficient knowledge of the neurological and physiological mechanisms that initiate, maintain, and terminate sleep, will reveal sleep’s basic function – sometimes enunciated as ‘‘functionandmechanismquestionsultimatelymerge.’’However,theproposedbasic function discussed below is unrelated to sleep’s neurological (brainstem activating systems) and physiological control mechanisms (see Kavanau, 1997). The latter are manifestedchieflybycyclicalterationsinbrainneuromodulatorysecretions(suchas acetylcholineandserotonin)(seeStickgold,1998)duringthefourprincipalvigilance states, that is, REM and NREM sleep, and active and restful wakefulness. Itisapropertyofbrainevolution,drivenbytheadaptiveadvantagesofefficiency, thatanygivenregionofthebraintypicallycarriesoutmorethanonefunction.This adaptation largely underlies the ‘‘fundamental dogma’’ of neuroscience, as characterized by Rauschecker (1995), namely, that long-term memories are stored by means of synaptic modifications in the same distributed assembly of brain structures that process and analyze the events and relations to be remembered (Squire, 1986; Ungerleider, 1995). In a striking example of such circuit multifunctionality, one not only becomes blind to colors (‘‘achromatopsia’’), after severedamagetobrainregionsthatprocesscolors,someofthosesoafflicteddonot even remember that colors exist (Zeki, 1999). 2.2. Restful waking, detailed focal vision, and conflicting brain activities Restful waking, including readiness, undoubtedly was the phylogenetically antecedentvigilancestatetoprimitivesleep(Kavanau,1997).Duringrestfulwaking, the brain continues to receive and process sensory inputs, and full vigilance is maintained, but there is no voluntary activity. Absence of voluntary activity amounts to reduced interference with other activities of the waking brain, of which sensory processing is a major component. Even when an activating stimulus is received during restful waking, it merely initiates a state of readiness, with lowered sensory thresholds. Restful waking evolved in many animals that previously were active continuously. For greatest effectiveness, periods of restful waking likely were relatively lengthy and spent in safe retreats. Inasmuch as daily light–dark cycles providenaturalconstrainingguidesforalternateperiodsofactivityandinactivity,at its inception, restful waking, in any given species, probably was channeled largely into lengthy nocturnal or diurnal periods. Vertebrates would already have been engaging in daily cycles of activity and restful waking when selective pressures for primitive sleep arose. Evolutionary progression toward primitive sleep would have begun when animals with comparatively simple lifestyles evolved increasing complexity and detailed focal vision (vision that recreates a complex scene). Such vision requires enormous amountsofneuralprocessing(Llina´sandPare´,1991)–thecombiningofaverygreat 4 J.L.Kavanau number of incredibly specific bits and pieces of visual features, formed by decompositionprocessesthatbegininthephotoreceptorcells(rodsandcones).This combininginvolvesvastlymore,andmorecomplex,operationsthanarerequiredby other sensory modalities. Despite its complexity and enormous requirements, visual processing is carried out largely at a low level, without visual attention (but not without potential interference with other waking brain activities). In the macaque monkey (Macaca fascicularis), for example, a complex mosaic covering roughly 60% of the brain’s surface regions is involved in visual processing (Van Essen et al., 1992). The mammalian visual system is said to have a nearly infinite capacity to recognize patterns and objects. Without focusing attention on any specific region of a scene, one becomes aware of the space-filling presence of almostlimitlessnumbersofobjects,ofallsizes,shapes,andcolors,inallimaginable relationships – with everything in view simultaneously, and despite, or perhaps facilitated (Ross and Ma-Wyatt, 2004) by, saccades at (cid:1)3/s. In the ancient times when such detailed focal vision was being acquired, animals would have been engaging increasingly in multifarious activities and ‘‘wide-ranging’’ movements, frequentlyexposedtonewvisualexperiences.Insuchalifestyle,lifelongretentionof greatly increased stores of memories would have been crucial. It has been postulated that, in animals achieving detailed focal vision, with the accompanyingneedsforlargestoresofmemories,theparallel-processingcapacityof the brain was becoming excessively taxed, because of developing conflicts between enormousandurgentdemandsofcomplexvisualanalysisandsplit-secondcontrolof movements, on the one hand, and non-urgent learning and memory processing, on theother(Kavanau,1997).Thebrainsoftheseanimalscouldnolongermeetcrucial, largely unpredictable, hazards and routine needs, while at the same time, meeting needs to acquire, establish (consolidate), and reinforce large stores of long-term memories, with all neural activities in given categories sharing circuitry in corresponding dedicated brain regions. In other words, an adaptation (circuit multifunctionality) that had conferred great efficiency before the evolution of detailed focal vision, would have become increasingly maladaptive as a more complex visual lifestyle evolved, had not compensating adaptations evolved in parallel, namely, restful waking at first, followed by primitive sleep. 2.3. Primitive sleep obviated potentially conflicting brain activities Theselectivepressurefortheoriginofprimitive sleepmayhavebeentheneedto ameliorate the developing conflicts discussed earlier, by achieving a more profound state of brain unresponsiveness to external occurrences during memory processing than exists during restful waking. By relieving the brain of extensive needs to process and respond to environmental, chiefly detailed visual, inputs during a portion of the 24-h cycle, memory processing could have proceeded without impediment during that portion. As a result, those mnemonic activities that could be delayed with minimal survival risk, such as establishing new memories and reinforcing existing long-term memories, came to be carried out during the newportion,namely,primitivesleep(Kavanau,1997).Itisareasonableassumption EvolutionaryAspectsofSleepandItsREMandNREMStates 5 that sleep in present-day reptiles has changed very little from the primitive sleep of their ancestors. In line with the above proposals, the reason why invertebrates lacking image-forming eyes, such as many mollusks, echinoderms, worms, and the like, need no sleep, is because their sensory input processing during activity and restful waking interferes minimally, or not at all, with other vital brain activities. As indicated above, these would be largely memory consolidation and processing, and other maintenance activities. In other words, because processing of non-visual sensory information engages much less brain tissue, and in a very much simpler manner than detailed visual input, it does not come into conflict with other vital brain activities. In this regard, with eyelids closed, or under anesthesia, region 18 of the feline visual cortex shows intrinsic patterns of EEG activity resembling those produced by certain visual stimuli (see Ringach, 2003). These patterns presumablyreflectongoingunimpededreinforcementofcomponentcircuitsofvisual memories. The key, overt, adaptive changes that accompanied selection for primitive sleep probably were: (a) to close eyelids that previously were transparent and purely protective, but were in the process of becoming increasingly opaque; and/or (b) to retire to secure quarters, often in dim light or darkness. With the exclusion of light, and without a need to process detailed visual inputs, and with correspondingly decreased attentiveness to other sensory inputs, the sleeping brain would have been almost totallyoccupied withsomeofthosepreviousneuralactivitiesofwakingthat could be delayed with minimal risk. Thattheprimitivesleepstatesubjectedanimalstogreaterrisksthanspendingthe sameperiodsawake,wouldnothavebeendetermining.Thecriticalfactor–vis-a`-vis natural selection – would have been, whether primitive sleep’s adaptive advantages outweighed the greater risks entailed. The proposed adaptive advantages were the maintenance of great efficiency of brain function, both awake and asleep – highly efficient sensory processing and responding when awake, and highly effective memory processing when asleep. Primitive sleep would have compensated for a gradually developing potential conflict, namely, the need to accomplish all these interrelated neural activities in partially shared circuitry during a continuous waking state. In this connection, Moorcroft (1989) made a general suggestion similar to that proposed here and earlier (Kavanau, 1996, 1997), namely, that sleep provides a period when certain activities ‘‘can occur most easily and most efficiently.’’ In a similar vein, Maquet (2001) suggested that ‘‘[s]leep could be a privileged period for memory consolidation....’’ Some mental dysfunctions may exert their influences through reducing the efficiency of brain operations. Thus, the cerebellum may expedite the automation of motor and cognitive skills. Rutherford (2003) proposes that cerebellar dysfunction slows or prevents this automation. ‘‘Either circumstance could take a toll on cerebral performance, affecting connections between the senses and physical functions as well as the ability to organize, create, and complete thoughts and tasks. This certainly seems to be the case for the cognitive and motor functioning of patients who have cerebellar dysfunctions.’’ 6 J.L.Kavanau In incipient stages of sleep’s evolution, the brain functions that now occur independently during waking and sleep probably occurred competitively. However, compelling evidence indicates that the conflicting needs now have become incompatible during wakefulness. Some memory consolidation involving detailed visual discriminations cannot occur during waking. It absolutely requires sleep (Gais et al., 2000; Stickgold et al., 2000). This unequivocal establishment of a specific vision-related activity that requires sleep lends strong support to the foregoing paradigm for the role of detailed focal vision in sleep’s origin. This paradigm already is persuasively supported by findings that sleep occurs only in animals with complex image-forming eyes, as opposed to eye spots and light-sensitive pigment cups and tubes, that to sleep, many animals must block visual input, by closing their eyelids or other means, and that, in some animals, unihemispheric sleep automatically ensues when one eyelid is closed (see Kavanau, 1997). One should not lose sight of the circumstance that, despite the potential neural processing conflicts referred to earlier, continuous dynamic interactions of sensory inputs with ongoing neural activities are intrinsic to waking brain function. Even at its most basic levels the central nervous system (CNS) is not organized to yield particular responses to particular stimuli, but instead, to accomplish particular objectives. Rather than mirroring the external world, the CNS embodies a dialog between internal states, generated by intrinsic electrical activity of nerve cells and their connectivity, and sensory information. With respect to the visual input, which is of greatest interest here, activity in the feline cortex depends not only on the nature of a visual stimulus, but also on the cortical state at the time of stimulation (see Ringach, 2003). Sensory stimuli gain their significance by virtue of triggering a preexisting disposition of the brain to be active in a particular way. If a stimulus is not put in the context of thalamocortical reality by becoming correlated temporally with ongoing neural activity, it does not exist as a functionally meaningful event (Llina´s and Pare´, 1991; additional Refs. in Kavanau, 1997). This proposal for the origin and function of primitive sleep does not preclude subsequent or concomitant evolution of secondary functions that may have become essential. Indeed, for birds and most mammals, secondary functions of sleep come into play, some of which are discussed below, as well as deep- seated rhythmical changes that engage many physiological systems (Vertes, 1990; Everson, 1995). 2.4. Vertebrates that never sleep The lifestyles of vertebrates that never sleep are fully consonant with the above proposals. As would be expected, since genetically blind, cold-blooded vertebrates that live in caves have no visual input, there can be no visual processing conflict, so no sleep is needed. However, many continuously swimming fishes that possess detailed focal vision, such as tunas and many sharks, do not sleep, either. Their lack of a need for sleep can be attributed to their lifestyle, in which needs for processing both sensory information, predominantly visual, and long-term EvolutionaryAspectsofSleepandItsREMandNREMStates 7 experiential memories, are greatly reduced and, therefore, do not conflict with each other. These reductions owe to the following aspects of shark and tuna behavior andecology:(1)theirvisualinputisgreatlyreducedorabsentduringlengthyperiods of both diurnal and nocturnal activity; (2) schooling greatly reduces needs for environmental sensory information, particularly visual; (3) their circuitry for most inherited memories needs no supplemental reinforcement, because it is maintained through almost continuous use; and (4) because they lead a comparatively routine, monotonousexistenceinessentiallyfeatureless,openwaters,theyacquire,andhave need to reinforce, relatively few experiential memories. Analogous circumstances could account for the ability of migratory birds to fly for days without rest or sleep (Kavanau, 1998a, 2001a). 2.5. Need for sleep in congenitally and adventitiously blind mammals In view of the proposed role of detailed focal vision in the evolution of sleep, some comments are in order concerning the need for sleep in congenitally and adventitiously blind mammals. The resolution of the seeming disparity hinges on three principal factors: (a) the same amount of ‘‘visual’’ cortex, in need of extensive reinforcement, exists inboth sighted andblind animals; (b)thehigh metabolicrates of endothermy (loosely speaking, warm-bloodedness), with an accompanying relatively high rate of degradation and functional depletion of molecules essential for synaptic function, and a correspondingly more frequent need for replenishment of these molecules by reinforcement during sleep; and (c) the great plasticity and high adaptability of ‘‘visual’’ cortices which, when unused for vision, take over the implementationofothersensorymodalities(Rauschecker,1995).Secondaryrolesof sleep–rest,rejuvenation,etc.–farremovedfromthefunctionsoforigin,alsocome into play. Concerning item (a), many neurological and neurophysiological studies in non-genetically blind humans and/or cats have given uniform results. Although the optic nerve, optic chiasm, and lateral geniculate nucleus may degenerate, neocortical ‘‘visual’’ regions undergo no size reduction and show no evidence of organic change. They remain highly active, metabolically and electrically, with highest activity in the striate and prestriate regions (Wanet-Defalque et al., 1988; Yaca et al., 1999; additional Refs. in Kavanau, 2001b). Moreover, in monkeys and cats visually deprived since birth, the electrical activity that develops spon- taneously in neurons of ‘‘visual’’ regions resembles that in non-deprived animals (Roder et al., 1997). The observations of item (a) probably are accounted for partly by the development of cross-modal compensatory plasticity encompassed under item (c). Evidence has been mounting of a great potential for such plasticity in vertebrate visualneocorticalregions,manyofwhichtakeonsupplementalauditoryandtactile functions. Many visual regions also normally process auditory and somatosensory inputs(Rolls,1991;VanEssenetal.,1992).Thesecircumstancesarewellexemplified by human cortical visual regions. Thus, the level of activity in the primary and secondary ‘‘visual’’ cortices of congenitally and adventitiously blind subjects during

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