Table Of ContentTABLE 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
