All-optical deconstruction of thalamic control of sleep-wake states.

ended

While the functions of sleep are still a matter of debate and may include memory consolidation, brain clearance, anabolism and plasticity, the neural substrates of sleep and wake states are the subject of intense study. Successive sleep-wake cycles rely on an appropriate balance between sleep-promoting nuclei of the brain located in the anterior hypothalamus and, arousal-promoting nuclei from the posterior hypothalamus and the brainstem. My laboratory identified different subsets of hypothalamic cells that controls wakefulness and rapid-eye movement (also called paradoxical) sleep using optogenetics in combination with high-density electrophysiology in freely-behaving mice. We further identified their connections with (and functional modulation of) other sleep-wake circuits throughout the brain. Although we and others have dissected important subcortical and cortical sleep-wake circuits in the brain, the precise mechanism bridging sub-cortical circuits to thalamic and cortical networks remains unclear. I hypothesizes that the thalamus represents a hub that integrates sleep-wake inputs of both subcortical and cortical origin into stable sleep-wake states, through topographically distinct sub-cortical inputs and temporally precise circuit dynamics (spiking pattern, coherence). To test this hypothesis, my experimental objectives are divided into three specific aims: 1) Identify the simultaneous cellular dynamics of thalamo-cortical network activity across sleep-wake states (Observational approach; Year 1-3) 2) Characterize the subcortical modulation of thalamic structures across sleep-wake states (Perturbational approach; Year 2-4) 3) Study the role of TRN/CMT circuits in sleep homeostasis and consciousness (Functional approach; Year 4-5) Completion of this project will provide a mechanistic perspective on sub-cortical, thalamo-cortical and cortical control of sleep-wake states, sleep homeostasis and consciousness in the mammalian brain.