A Thalamocortical Perspective on Sleep Spindle Alterations in Neurodevelopmental Disorders.

Purpose of Review: Neurodevelopmental disorders are a group of conditions that affect the development and function of the nervous system, typically arising early in life. These disorders can have various genetic, environmental, and/or neural underpinnings, which can impact the thalamocortical system. Sleep spindles, brief bursts of oscillatory activity that occur during NREM sleep, provide a unique in vivo measure of the thalamocortical system. In this manuscript, we review the development of the thalamocortical system and sleep spindles in rodent models and humans. We then utilize this as a foundation to discuss alterations in sleep spindle activity in four of the most pervasive neurodevelopmental disorders-intellectual disability, attention deficit hyperactivity disorder, autism, and schizophrenia. Recent Findings: Recent work in humans has shown alterations in sleep spindles across several neurodevelopmental disorders. Simultaneously, rodent models have elucidated the mechanisms which may underlie these deficits in spindle activity. This review merges recent findings from these two separate lines of research to draw conclusions about the pathogenesis of neurodevelopmental disorders. Summary: We speculate that deficits in the thalamocortical system associated with neurodevelopmental disorders are exquisitely reflected in sleep spindle activity. We propose that sleep spindles may represent a promising biomarker for drug discovery, risk stratification, and treatment monitoring.

A role for spindles in the onset of rapid eye movement sleep.

Sleep spindle generation classically relies on an interplay between the thalamic reticular nucleus (TRN), thalamo-cortical (TC) relay cells and cortico-thalamic (CT) feedback during non-rapid eye movement (NREM) sleep. Spindles are hypothesized to stabilize sleep, gate sensory processing and consolidate memory. However, the contribution of non-sensory thalamic nuclei in spindle generation and the role of spindles in sleep-state regulation remain unclear. Using multisite thalamic and cortical LFP/unit recordings in freely behaving mice, we show that spike-field coupling within centromedial and anterodorsal (AD) thalamic nuclei is as strong as for TRN during detected spindles. We found that spindle rate significantly increases before the onset of rapid eye movement (REM) sleep, but not wakefulness. The latter observation is consistent with our finding that enhancing spontaneous activity of TRN cells or TRN-AD projections using optogenetics increase spindle rate and transitions to REM sleep. Together, our results extend the classical TRN-TC-CT spindle pathway to include non-sensory thalamic nuclei and implicate spindles in the onset of REM sleep.

Circadian VIPergic Neurons of the Suprachiasmatic Nuclei Sculpt the Sleep-Wake Cycle.

Although the mammalian rest-activity cycle is controlled by a "master clock" in the suprachiasmatic nucleus (SCN) of the hypothalamus, it is unclear how firing of individual SCN neurons gates individual features of daily activity. Here, we demonstrate that a specific transcriptomically identified population of mouse VIP+ SCN neurons is active at the "wrong" time of day-nighttime-when most SCN neurons are silent. Using chemogenetic and optogenetic strategies, we show that these neurons and their cellular clocks are necessary and sufficient to gate and time nighttime sleep but have no effect upon daytime sleep. We propose that mouse nighttime sleep, analogous to the human siesta, is a "hard-wired" property gated by specific neurons of the master clock to favor subsequent alertness prior to dawn (a circadian "wake maintenance zone"). Thus, the SCN is not simply a 24-h metronome: specific populations sculpt critical features of the sleep-wake cycle.

Thalamic dual control of sleep and wakefulness.

Slow waves (0.5-4 Hz) predominate in the cortical electroencephalogram during non-rapid eye movement (NREM) sleep in mammals. They reflect the synchronization of large neuronal ensembles alternating between active (UP) and quiescent (Down) states and propagating along the neocortex. The thalamic contribution to cortical UP states and sleep modulation remains unclear. Here we show that spontaneous firing of centromedial thalamus (CMT) neurons in mice is phase-advanced to global cortical UP states and NREM-wake transitions. Tonic optogenetic activation of CMT neurons induces NREM-wake transitions, whereas burst activation mimics UP states in the cingulate cortex and enhances brain-wide synchrony of cortical slow waves during sleep, through a relay in the anterodorsal thalamus. Finally, we demonstrate that CMT and anterodorsal thalamus relay neurons promote sleep recovery. These findings suggest that the tonic and/or burst firing pattern of CMT neurons can modulate brain-wide cortical activity during sleep and provides dual control of sleep-wake states.

Sleep & metabolism: The multitasking ability of lateral hypothalamic inhibitory circuitries.

The anatomical and functional mapping of lateral hypothalamic circuits has been limited by the numerous cell types and complex, yet unclear, connectivity. Recent advances in functional dissection of input-output neurons in the lateral hypothalamus have identified subset of inhibitory cells as crucial modulators of both sleep-wake states and metabolism. Here, we summarize these recent studies and discuss the multi-tasking functions of hypothalamic circuitries in integrating sleep and metabolism in the mammalian brain.

Hypothalamic feedforward inhibition of thalamocortical network controls arousal and consciousness.

During non-rapid eye movement (NREM) sleep, synchronous synaptic activity in the thalamocortical network generates predominantly low-frequency oscillations (<4 Hz) that are modulated by inhibitory inputs from the thalamic reticular nucleus (TRN). Whether TRN cells integrate sleep-wake signals from subcortical circuits remains unclear. We found that GABA neurons from the lateral hypothalamus (LHGABA) exert a strong inhibitory control over TRN GABA neurons (TRNGABA). We found that optogenetic activation of this circuit recapitulated state-dependent changes of TRN neuron activity in behaving mice and induced rapid arousal during NREM, but not REM, sleep. During deep anesthesia, activation of this circuit induced sustained cortical arousal. In contrast, optogenetic silencing of LHGABA-TRNGABA transmission increased the duration of NREM sleep and amplitude of delta (1-4 Hz) oscillations. Collectively, these results demonstrate that TRN cells integrate subcortical arousal inputs selectively during NREM sleep and may participate in sleep intensity.

Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.