Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Circuit-based Interrogation of Sleep Control


Nature  538, 51–59 (06 October 2016)

Circuit-based interrogation of sleep control

Franz Weber  & Yang Dan

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA


Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep. The ability to initiate and terminate sleep on command will also help us to elucidate its functions within and beyond the brain.

Sleep is a seemingly unproductive behavioural state that takes up a large proportion of our lives, but insufficient sleep can profoundly impair our cognitive performance during wakefulness. Long-term sleep deprivation is also linked to many other health problems, including obesity and cardiovascular diseases. At the behavioural level, sleep has been observed widely across the animal kingdom, including in worms and flies, as well as vertebrates. However, the existence of two distinct types of sleep—rapid eye movement (REM) sleep and non-REM (NREM) sleep—was previously thought to be restricted to mammals and birds and has only recently been identified in reptiles.

Wakefulness,    NREM sleep    and REM sleep can be clearly distinguished based on electroencephalogram (EEG) and electromyogram (EMG) recordings, making sleep a directly quantifiable behaviour. During wakefulness, the EEG exhibits high-frequency, low-amplitude activity (‘desynchronized EEG’), and the EMG shows high muscle tone. In contrast, the EEG during NREM sleep is dominated by high-amplitude, low-frequency (0.5–4.5 Hz) activity (‘synchronized EEG’) together with sleep spindles (waxing and waning of 9–15 Hz oscillations lasting for a few seconds).    REM sleep is associated with vivid dreaming; it is also called paradoxical sleep, as it is characterized by desynchronized EEG    resembling that during wakefulness,    but the EMG shows a complete paralysis of postural muscles. The proportions of time the animal spends in wakeful,    NREM    and REM states and the temporal patterns of state transitions vary widely across species. However, there are some well-conserved features. For example, animals normally enter REM sleep    from NREM sleep    but not directly from wakefulness.

Circadian modulation of sleep depends critically on the suprachiasmatic nucleus (SCN) in the hypothalamus, the master pacemaker of the whole organism. Lesion of the SCN or its downstream target regions eliminates the daily rhythm of sleep without markedly affecting its amount, suggesting that the SCN is not part of the core circuit for sleep generation, but it regulates the circadian timing of sleep.

SCN neuron spiking was shown to play a key role in regulating both the molecular clock and behavioural rhythm, as optogenetic activation or suppression of SCN activity was sufficient to alter the phase and periodicity of clock gene expression and of the sleep–wake cycle. The firing rates of SCN neurons are high during the subjective day and low during the night, regardless of whether the animal is diurnal or nocturnal. Such circadian variation of electrical activity is controlled by both the molecular clock driven by multiple transcriptional/translational feedback loops that regulates the intrinsic excitability of SCN neurons    and the synaptic inputs    signalling the light–dark cycle of the environment. Notably, in vivo multiunit recordings showed that,    superimposed on the slow circadian variation,    SCN neuron firing rates also change with the sleep–wake states on a timescale of seconds. This is probably caused by synaptic inputs from neurons involved in sleep–wake regulation, such as cholinergic and monoaminergic neurons. Given such ultradian firing rate modulations, it would be interesting to know whether SCN activity can exert rapid influences on brain states in the order of seconds to minutes, in addition to its well-known circadian effect in the order of hours. In addition, the SCN consists of multiple cell types including vasoactive intestinal peptide-positive and arginine vasopressin-positive cells. Whether different types of SCN neurons play distinct roles in sleep–wake regulation remains to be investigated.

The SCN    projects to multiple target regions    to coordinate a variety of physiological functions.    Among these targets, the dorsomedial hypothalamic nucleus (DMH) may play a particularly important role in sleep–wake regulation. Lesion of the DMH largely eliminated the sleep–wake circadian rhythm. In addition, a study using a pseudo-rabies virus for trans-synaptic retrograde tracing showed that the DMH provides an important relay from the SCN to the noradrenergic Locus Coeruleus (LC), which contains wake-promoting noradrenergic neurons. Importantly, the DMH comprises both glutamatergic and GABAergic neurons that appear to innervate both sleep- and wake-promoting circuits. Understanding the functional organization of this structure and how it mediates the circadian modulation of sleep again requires cell-type-specific recording, manipulation and circuit mapping.

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