Brainstem circuitry for sleep-wake control

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PROJECT SUMMARY/ABSTRACT It is now clear that poor sleep quality has dramatic health consequences, yet sleep medicine is still in great need for safe and efficient sleep aids. Recent major advances in understanding how the brain regulates sleep- wake cycles have opened new lines of investigations, revealing a complex regulatory network for non-rapid eye movement (NREM) sleep control that includes multiple new sleep-promoting neuronal populations. A series of recent work by our laboratory have demonstrated the critical importance of parafacial zone (PZ) neurons in sleep induction and maintenance, and of the GABAergic neurons in this region in promoting the deep, restorative stage of NREM sleep known as slow-wave sleep (SWS). There is a fundamental gap, however, in understanding the cellular and synaptic circuit basis by which PZ neurons control sleep. The long-term goal is to understand the cellular and circuit bases by which PZ neurons promote sleep. The central hypothesis is that the brainstem contains a sub-population of PZ GABAergic neurons that are both sufficient and necessary for the generation of SWS and cortical slow-wave activity (SWA). The rationale for the proposed research is that understanding how the PZ promotes sleep is a critical first step towards manipulating this sleep-promoting circuit and will lead to subsequent translational studies centered on the PZ aimed at reducing the burden of sleep disruption associated with sleep-wake disorders but also other neurologic disorders. Our hypothesis will be tested by pursuing two specific aims: 1) uncover a PZ GABAergic sub-population that is specifically sleep promoting; and 2) elucidate the neuronal circuits by which PZ GABAergic neurons directly influence cortical activity. Guided by strong preliminary data, in aim 1, we will uncover the role of PZ Parvalbumin expressing GABAergic neurons in sleep- wake control using a combination of genetically-driven lesions, chemogenetic/optogenetic activation/inhibition, fiber photometry and neuronal tracing; and in Aim 2, we will uncover a direct pathway by which the PZ directly affects thalamo-cortical activity and drives the SWA characteristic of SWS, using in vitro electrophysiology, optogenetic activation of PZ GABAergic projections to the thalamus, in vivo Ca2+ imaging of PZ GABAergic neurons projecting to the thalamus, and chemogenetic activation of PZGABA in thalamic lesioned mice. The approach is intellectually and technically innovative because it represents a new and substantive substrate of understanding sleep regulation and because it employs a novel combination of state-of-the-art approaches. The proposed research is significant because it is expected to provide critical knowledge of the molecular and cellular mechanisms by which sleep is regulated. Ultimately, such knowledge is expected to guide the development of therapeutic and interventional strategies to better regulate sleep-wake behavior and to reduce the burden associated with sleep disruption, not only associated with sleep disorders but also with many neurological and psychological disorders that represent a tremendous cost in the United States and worldwide.