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 1, 2. 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, 0.5-4.0 Hz, SWA), arising from synchronous fluctuations of the membrane potential in large neuronal populations 3.
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 4. However, evidence has accumulated that neither wake nor sleep are always global 2. 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 5, 6. Evidence derived from this new approach implies a crucial role for sleep in neural plasticity, local synaptic 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 2, 7. 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 5, 6. 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 5, 6, 8, 9, which might underlie the well-known psychomotor and cognitive deficits typical for sleep deprivation 10.
Surprisingly, while homeostatic regulation of sleep is a precise, ubiquitous and basic phenomenon found in all animals species studied up-to-date 11, 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 12, activity-dependent release of cytokines 13 and synaptic plasticity 2, 14. 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 lead to 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 rarely lasts spontaneously for more than several hours or a few days 11, 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 neuromodulatory (such as monoaminergic, glutamatergic, GABAergic and cholinergic) action on the neocortex 4. Importantly, the same neuromodulatory 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 EEG. Wakefulness in rodents is traditionally distinguished from NREM sleep by the virtual absence of large-amplitude EEG slow waves, and by the presence of theta (~7-9 Hz) activity 15, presumably arising as a result of physical spread of theta activity from the hippocampus 15, 16. Hippocampal theta activity has been related to voluntary activity, arousal, attention, the representation of spatial position, learning and other behaviors or functions 16-18. 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 19. 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 20-22. 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 4 and intracortical and cortico-subcortical interactions 23, but also by behavior 24, 25 and processing of incoming external stimuli 26.
Cortical neuronal firing patterns in wakefulness and another activated state, REM sleep, are profoundly and characteristically different from those in NREM sleep 3. Cortical neuronal firing activity is generally slower in NREM sleep compared to both wakefulness and REM sleep 3, 27. Moreover, independent firing of neurons in wakefulness is replaced with regular synchronous bursts of action potentials during sleep 27. During NREM sleep the neocortex is functionally disconnected from the surroundings (environment), and the most distinctive feature of the EEG is the near-synchronous occurrence of slow waves in all or most cortical areas 28. The fundamental cellular phenomenon underlying sleep EEG slow waves is the slow oscillation, comprised of a depolarized UP state and a hyperpolarized DOWN state, during which the cortical cell ceases firing 3, 29, 30. In vivo, in vitro and in computo evidence indicates that the DOWN state of the slow oscillation is the result of disfacilitation (i.e. a lack of synaptic input), rather than of active inhibition 31-33. The global cortical pattern of activity in NREM sleep consists of an alternation between periods of elevated neuronal firing (ON periods), lasting several hundreds of milliseconds, and shorter periods of generalized silence, corresponding to the negative phase of surface EEG slow waves. However, while it is well known that brain activity is different depending on whether you are awake or asleep, less is known about whether and why there is a difference in brain activity depending on for how long you have been awake or asleep before.
2. Preceding history: global and local regulation of sleep
The function of sleep is likely to be closely related to sleep regulation. It is well known that sleep is regulated homeostatically 34, e.g. sleep loss is compensated by subsequent sleep intensity. In most species, sleep pressure increases as a function of time spent awake and decreases in the course of sleep. The best characterized physiological indicator of sleep-wake history is the level of cortical EEG SWA during NREM sleep 34. In mammals, sleep SWA is high in early sleep and after sleep deprivation, when sleep pressure is increased physiologically, and decreases progressively to reach low levels in late sleep 35, 36. The prevailing view is that brain states are regulated in a global fashion. However, evidence has been accumulated to indicate that neither wake nor sleep are always global 2. Over the last two decades multiple studies have shown that during spontaneous sleep SWA is not uniform across the cortical surface, but shows topographic gradients. In both humans and animals, SWA is more intense in the frontal derivations, especially in early sleep or after sleep deprivation 37. Moreover, peripheral stimulation or the spontaneous use of circumscribed cortical areas leads to more intense local EEG slow waves 7, 38, 39. Such observations suggested that not only waking duration per se, but also specific waking activities affect the intensity of subsequent sleep, and indicate that sleep may play a local restorative function. Surprisingly, while sleep homeostasis is a precise, ubiquitous and basic feature of sleep in mammals and birds, the specific mechanisms underlying the sleep regulatory processes remain unknown.
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