ЖУРНАЛ ВЫСШЕЙ НЕРВНОЙ ДЕЯТЕЛЬНОСТИ, 2013, том 63, № 1, с. 13-23
^ ОБЗОРЫ,
ТЕОРЕТИЧЕСКИЕ СТАТЬИ
УДК 612.821.6
Cortical Neuronal Mechanisms of Sleep Homeostasis
© 2013 Vladyslav V. Vyazovskiy
University of Surrey, Guildford, the United Kingdom, e-mail: vyazovskiy@gmail.com
The longer we are awake, the deeper is our subsequent sleep. On the other hand, the shorter and more fragmented is our sleep, the more difficult it is for us to maintain wakefulness and stable cognitive performance the next day. This relationship between wakefulness and subsequent sleep becomes especially apparent after sleep deprivation or during chronic sleep restriction, which is experienced by millions of people in our society, as well as in multiple neurological, respiratory and other chronic diseases. Invariably, poor sleep leads to fatigue, sleepiness, marked cognitive deficits and impaired mood. The crucial question is what happens to the brain after a period of being awake or asleep, and where in the brain and why do these changes occur. This review summarizes information about neurophysiological substrates of sleep homeostatic processes at the cellular and network levels. It is suggested that sensory, behavioral and cognitive deficits after sleep deprivation resulting from the imbalance between local and global neuronal interactions can be reversed only by physiological sleep.
Keywords: sleep, waking, sleep homeostasis, neocortex, sleep deprivation, EEG, slow waves.
КОРКОВЫЕ НЕЙРОННЫЕ МЕХАНИЗМЫ ГОМЕОСТАТИЧЕСКИХ ПРОЦЕССОВ СНА
© 2013 г. В. В. Вязовский
Университет Суррея, Великобритания, e-mail: vyazovskiy@gmail.com Поступила в редакцию 15.05.2012 г.
Принята в печать 19.10.2012 г.
Известно, что чем дольше мы бодрствуем, тем глубже наш последующий ночной сон. С другой стороны, чем короче и более фрагментирован наш сон, тем сложнее на следующий день поддерживать устойчивое бодрствование и успешную когнитивную деятельность. Эти отношения между сном и последующим бодрствованием после депривации сна или хронического недостатка сна наблюдаются как у миллионов здоровых людей, так и при различных хронических заболеваниях. Недостаток сна является причиной возникновения состояния утомления, повышенной сонливости, когнитивных расстройств и ухудшения настроения. Фундаментальный вопрос современной нейробиологии: что происходит с мозгом после длительного периода бодрствования и отсутствия сна и в каких областях мозга, когда и какие изменения происходят? Настоящий обзор обобщает информацию о нейрофизиологическом субстрате гомеостати-ческих процессов сна на клеточном и нейросетевом уровнях. Выдвинуто предположение, что сенсорные, поведенческие и когнитивные нарушения, наблюдаемые после депривации сна, возникают в результате дисбаланса между локальными и глобальными нейронными взаимодействиями, которые могут быть нормализованы только в процессе физиологического сна.
Ключевые слова: сон, бодрствование, гомеостаз сна, кора головного мозга, депривация сна, ЭЭГ, медленные волны.
DOI: 10.7868/S0044467713010176
Throughout the life span every animal spontaneously goes through a sequence of distinct behavioral and brain states. One subdivision of these
states is in wakefulness and sleep. Sleep is a heterogeneous state, subdivided into non-rapid eye movement (NREM) sleep, also called slow-wave
sleep, and REM sleep. Waking is also anything but a steady state, varying on a time scale of hours, minutes or even seconds from attentive alert state to a largely disconnected from the environment state of restful drowsy waking. However, the activity of the brain does not only reflect the current level of arousal, ongoing behavior or involvement in a specific task, but also is influenced by what kind of activity, and how much sleep and waking occurred previously. Indeed, being awake and asleep do not alternate at random, but preceding sleep-wake history and the circadian clock govern the global and local changes in brain state [10, 43]. For example, prolonged waking is invariably followed by deep restorative sleep, while NREM sleep episodes alternate on a regular basis with REM sleep periods. The duration and quality of waking predicts subsequent sleep intensity, reflected in high-amplitude electroencephalography (EEG) slow waves (slow-wave activity, SWA), arising from synchronous fluctuations of the membrane potential in large neuronal populations [77].
The classical neuroscience view is that brain states are regulated in a global fashion by a set of subcortical neuromodulatory nuclei, projecting to the thalamus and widely across the neocortex and/or modulating the activity of each other [39]. However, evidence has accumulated that neither wake nor sleep are always global [43]. When we zoom-in on the activity of individual cortical neurons and neuronal populations, we see that while some neurons are irregularly active (ON), as is typical for waking, others may stay silent (OFF), as during sleep, even when the animal is behaviorally awake, and vice versa [92, 93]. Evidence derived from this new approach implies a crucial role for sleep in neural plasticity, local syn-aptic recovery processes and, ultimately, cognitive function. Interestingly, it was found that specific behaviors or peripheral stimulation during waking results in local, use-dependent changes in sleep EEG SWA, when some cortical regions "sleep" more intensely than others, depending on their preceding activity [43, 88]. Such changes may arise at the level of cortical neuronal circuits, as it has been shown that early intense sleep, when slow waves are large and frequent, appeared to be associated with short, intense neuronal ON periods, alternating frequently with relatively long OFF periods [92, 93]. Moreover, staying awake does not only lead to intense subsequent restorative sleep, but also to specific changes in the wake EEG and cortical neuronal firing [47, 92, 93, 96], which might underlie the well-known
psychomotor and cognitive deficits typical for sleep deprivation [26].
Surprisingly, while homeostatic regulation of sleep is a precise, ubiquitous and basic phenomenon found in all animals species studied up-to-date [81], its underlying mechanisms are still unknown. There are several candidate mechanisms which are believed to be implicated in sleep need. Among those are regulation of brain metabolism [65], activity-dependent release of cytokines [61] or synaptic plasticity [43, 82]. Several specific questions remain unanswered and should become the primary targets of future research. It is unclear at what level sleep-need accumulates and where sleep is initiated: e.g. individual neurons, local or distributed neuronal populations, cortical or subcortical regions, or specific neuronal subtypes? Moreover, it is still unknown which molecular, cellular and network mechanisms underlie the need for sleep, and what happens in the brain during waking that necessitates the occurrence of sleep. Finally, very little is known about how the changes in brain activity incurred during normal waking or sleep deprivation translate in the well-known behavioral and cognitive deficits.
1. BRAIN ACTIVITY IN WAKING AND SLEEP
A fundamental difference between wakefulness and sleep is the extent to which the brain is engaged in the acquisition and processing of information. In all species carefully studied so far, waking and sleep alternate on a regular basis and continuous wakefulness never lasts spontaneously for more than several hours or a few days [81], suggesting that sleep is necessary and it serves a vital role. The maintenance of waking and sleep states is regulated by the activity arising from several subcortical structures in the brainstem, hypothalamus and basal forebrain, which provide neuro-modulatory (such as monoaminergic, glutamater-gic, GABAergic and cholinergic) action on the neocortex [39]. Importantly, the same neuromodu-latory systems are crucially involved in attention, cognition, behavior and many other aspects of the regulation of internal states and the interaction of the brain with the outside world.
The behavioral or vigilance state of an animal is usually reflected in the cortical electroencephalogram (EEG). Wakefulness in rodents is traditionally distinguished from non-rapid eye movement (NREM) sleep by the virtual absence of large-amplitude EEG slow waves, and by the presence of theta (~7—9 Hz) activity [98], pre-
sumably arising as a result of physical spread of theta activity from the hippocampus [32, 98]. Hippocampal theta activity has been related to voluntary activity, arousal, attention, the representation of spatial position, learning and other behaviors or functions [15, 32, 62]. Based on phase-analysis and pharmacological studies it has been postulated that there is more than one generator and more than one type of theta activity in the hippocampus [68]. The functional significance of hippocampal theta activity is still unclear, but it can be highly relevant for various aspects of behavior and cognition given the complex interactions between the cortex and hippocampus during sleep and waking [11, 14, 71]. Apart from the EEG, the activated pattern of brain activity during waking is also apparent at the level of firing of cortical neurons. Overall, neuronal discharge in waking is largely fast and irregular, although it is determined strongly by behavior and involvement in specific tasks. The cortical activity in awake animals is generated not only by ascending influences from specific wake-promoting areas [39] and intracortical and cortico-subcortical interactions [12], but also by behavior [64, 95] and processing of incoming external stimuli [72].
Cortical neuronal firing patterns in wakeful-ness and another activated state, rapid eye movement (REM) sleep, are profoundly and characteristically different from those in NREM sleep [77]. Cortical neuronal firing activity is generally slower in NREM sleep compared to both wake-fulness and REM sleep [59, 77]. Moreover
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