The sub-cortical structures regulating slow-wave-sleep (SWS) and its electroencephalogram (EEG) correlate are incompletely understood. Continued existence of this fundamental knowledge gap represents an important problem because it reduces our ability to modulate or appropriately manipulate the brain's sleep circuitry and hampers our ability to treat and alleviate the physiological disorders that result from sleep disruption. My long- term goal is to understand how neurons in the medullary parafacial zone (PZ) contribute to the regulation of SWS and cortical slow-wave-activity (SWA), the latter of which is linked to fundamental neurobiological processes like memory consolidation, synaptic homeostasis and cortical plasticity. The objectives in this particular application is to determine ) if selective activation of GABAergic PZ neurons promotes SWS and cortical SWA in freely behaving animals;2) how GABAergic PZ neurons are functionally, synaptically connected with circuitry capable of modulating the cortical EEG;and 3) how other non-GABAergic PZ neurons might contribute to the regulation of SWS and cortical SWA. The central hypothesis is that subpopulations of GABAergic and non-GABAergic PZ neurons comprise a delimited node of SWS-promoting neurons, which generate SWS and cortical SWA through ascending projections to the parabrachial nucleus and basal forebrain. The rationale for the proposed research is that identifying the relevant PZ neurons that regulate SWS and cortical SWA represents a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with sleep disorders. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) using a newly developed and genetically targeted technique, determine if acute and selective activation of GABAergic Parafacial Zone (PZ) neurons is capable of generating SWS and cortical SWA in freely behaving animals;2) using a combination of genetically targeted mapping and optogenetics, determine the synaptic basis by which GABAergic PZ neurons potently drive SWS and SWA in vivo;3) using a new cre-driver mouse line and similar techniques to those employed in Aims 1 and 2, determine if non-GABAergic PZ neurons contribute to the regulation of SWS and cortical SWA. The approach is intellectually and technically innovative because it represents a new and substantive departure from contemporary circuit models of sleep regulation and because it employs a novel combination of newly developed and validated genetically-driven approaches. The proposed research is significant, because it is expected to vertically advance and expand understanding of the cellular and synaptic mechanisms by which brain sleep is generated and the role of the PZ in this regulation. Ultimately, such knowledge has the potential to inform the development of treatments to reduce the dysfunction and negative health effects experienced by a growing number of patients with sleep disorders in the United States.

Public Health Relevance

The proposed research is relevant to public health because understanding the synaptic and cellular mechanisms by which the brain generates sleep is ultimately expected to increase understanding of the pathogenesis of sleep-based disorders. Disrupted sleep has been linked with neuropsychiatric and neurodegenerative disorders, the pathogenesis of cardiometabolic disease and obesity. Thus 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 burdens of human disability, for a wide range of sleep, metabolic, neuropsychiatric and neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Special Emphasis Panel (ZMH1-ERB-L (02))
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Desmond, Nancy L
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Beth Israel Deaconess Medical Center
United States
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Anaclet, Christelle; Ferrari, Loris; Arrigoni, Elda et al. (2014) The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat Neurosci 17:1217-24