Sleep and neuropsychiatric illness

Dopaminergic ventral tegmental area (VTA) neurons are critically involved in a variety of behaviors that rely on heightened arousal, but whether they directly and causally control the generation and maintenance of wakefulness is unknown. We recorded calcium activity using fiber photometry in freely behaving mice and found arousal-state-dependent alterations in VTA dopaminergic neurons. We used chemogenetic and optogenetic manipulations together with polysomnographic recordings to demonstrate that VTA dopaminergic neurons are necessary for arousal and that their inhibition suppresses wakefulness, even in the face of ethologically relevant salient stimuli. Nevertheless, before inducing sleep, inhibition of VTA dopaminergic neurons promoted goal-directed and sleep-related nesting behavior. Optogenetic stimulation, in contrast, initiated and maintained wakefulness and suppressed sleep and sleep-related nesting behavior. We further found that different projections of VTA dopaminergic neurons differentially modulate arousal. Collectively, our findings uncover a fundamental role for VTA dopaminergic circuitry in the maintenance of the awake state and ethologically relevant sleep-related behaviors.

The principal neurons of the arousal and sleep circuits are comprised by glutamate and GABA neurons, which are distributed within the reticular core of the brain and, through local and distant projections and interactions, regulate cortical activity and behavior across wake-sleep states. These are in turn modulated by the neuromodulatory systems that are comprised by acetylcholine, noradrenaline, dopamine, serotonin, histamine, orexin (hypocretin), and melanin-concentrating hormone (MCH) neurons. Glutamate and GABA neurons are heterogeneous in their profiles of discharge, forming distinct functional cell types by selective or maximal discharge during (1) waking and paradoxical (REM) sleep, (2) during slow wave sleep, (3) during waking, or (4) during paradoxical (REM) sleep. The neuromodulatory systems are each homogeneous in their profile of discharge, the majority discharging maximally during waking and paradoxical sleep or during waking. Only MCH neurons discharge maximally during sleep. They each exert their modulatory influence upon other neurons through excitatory and inhibitory receptors thus effecting a concerted differential change in the functionally different cell groups. Both arousal and sleep circuit neurons are homeostatically regulated as a function of their activity in part through changes in receptors. The major pharmacological agents used for the treatment of wake and sleep disorders act upon GABA and neuromodulatory transmission.