Contemporary circuit models of sleep-wake regulation hold sleep to be an active process requiring the participation of specific sleep-promoting neurons, in particular those located in the preoptic forebrain. Recent work by our laboratory has identified a delimited node of GABAergic neurons in the medullary parafacial zone (PZGABA) that are both necessary and sufficient for normal slow wave sleep (SWS) and its electroencephalographic correlate, slow wave activity (SWA, 0.5-4Hz, also delta sleep). There is a fundamental gap however in understanding the cellular and synaptic circuit basis by which PZ GABAergic neurons trigger SWS and cortical SWA. The long-term goal is to understand the functional circuit basis by which PZGABA neurons generate and regulate SWS and SWA. The objective in this particular application is to extend our previous findings by defining the functional, synaptic neurocircuit basis by which PZGABA neurons trigger, and possibly maintain, SWS and cortical SWA. The central hypothesis is that PZGABA neurons promote SWS and SWA through direct inhibition of pontine parabrachial (PB) neurons, but that the ability to generate and maintain long, consolidate bouts of SWS may still require the influence of sleep-active preoptic neurons. The rationale for the proposed re- search is that identifying the circuit basis by which PZGABA neurons promote SWS and SWA represents a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with sleep- based disorders. Guided by strong preliminary data, our hypotheses will be tested by pursuing three specific aims: 1) determine the extent to which PB neurons that are post-synaptic targets of PZ neurons are sufficient and/or necessary for triggering SWS and cortical SWA; 2) identify the downstream 3rd-order targets of para- brachial neurons that themselves are post synaptic targets of PZGABA neurons; and 3) determine if activation of PZGABA neurons is sufficient to maintain SWS and/or if the influence of sleep-active preoptic neurons is also required. The approach is intellectually and technically innovative because it represents a new and substantive departure from contemporary models of sleep regulation and because it employs a novel combination of newly developed and validated approaches, including complimentary in vivo and in vitro chemico- and optogenetic based experiments. The proposed research is significant because it is expected to vertically advance and expand understanding of the cellular and circuit (synaptic) mechanisms underlying PZGABA regulation of SWS and cortical SWA. Ultimately, such knowledge has the potential to inform the development of therapeutic and interventional strategies to reduce the dysfunction and negative health effects experienced by a growing number of patients with sleep disorders in the United States and worldwide.
The proposed research is relevant to public health because understanding the synaptic and cellular mechanisms by which brainstem-based circuits regulate sleep is ultimately expected to increase understanding of how sleep and associated electroencephalographic rhythms are produced and maintained. As such, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that may yield improved pharmacologic approaches and interventional strategies, and thereby reduce the burden of human disability, in not only sleep-based disorders such as insomnia, but also in a host of neuropsychiatric, neurodegenerative and cardiovascular disorders in which sleep is disrupted, including depression and Parkinson's disease.
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