Molecular-Genetic Dissection of Subcortical Circuitry Regulating Arousal

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Project Summary There is a fundamental gap in understanding the circuit, cellular and synaptic bases by which the brain regulates and maintains neurobehavioral and electroencephalographic (EEG) arousal. This is an important problem because it not only reduces our ability to treat disorders of arousal, including restoration of consciousness in comatose individuals, but also impacts treatment and deeper understanding of many neuropsychiatric, neurodegenerative and neurological disorders that often include severe arousal disruption, including Alzheimer’s and Parkinson’s disease. We recently uncovered an especially critical and unexpected role for basal forebrain GABAergic (BFGABA) neurons in supporting wake and fast cortical rhythms. We further identified that wake- promoting glutamatergic (Vglut2+) neurons of the supramammillary hypothalamus (SUMVglut2) are a major source of excitatory input to the BF. The current proposal seeks to extend these findings by defining the molecular, cellular and synaptic bases by which the subcortical SUMVglut2  BFGABA circuit contributes to arousal and fast cortical rhythms in behaving animals. Building upon substantive preliminary data, our objective is the next step in pursuit of that goal, to define and characterize: 1) the cellular and synaptic bases by which the subcortical SUMVglut2  BFGABA circuit regulates neurobehavioral and EEG arousal, 2) all sources of presynaptic inputs to SUMVglut2 and BFGABA neurons and confirm functional synaptic connectivity within this subcortical network, spanning “input”SUMVglut2  BFGABA, and 3) the postsynaptic targets (“outputs”) of the SUMVglut2→BFGABA”outputs” circuit in the preoptic and lateral hypothalamus that drive arousal. Our long-term goal is to understand the cellular and synaptic bases by which the subcortical SUMVglut2  BFGABA circuit regulates behavioral and EEG arousal. The central hypothesis is that the SUMVglut2  BFGABA circuit is both necessary and sufficient for normal levels of brain arousal. The rationale for the proposed research is that identifying the cellular and synaptic bases by which the SUMVglut2  BFGABA circuit can modulate arousal levels is a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with disorders of arousal. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims. The approach is intellectually and technically innovative as it seeks to reveal the mechanistic basis by which this newly revealed subcortical circuit regulates brain arousal and because it employs a novel combination of newly developed and validated approaches. The proposed research is significant, as it is expected to vertically advance and expand understanding of the cellular and synaptic mechanisms by which a recently revealed subcortical circuit regulates arousal. Ultimately, such knowledge has the potential to inform the development of treatments for patients with arousal-based disorders, including those suffering neuropsychiatric, neurodegenerative and neurological disorders with severe arousal disruption, particularly those in which BF dysfunction has been implicated.