The magnocellular basal forebrain (BFmc) comprises cholinergic and non-cholinergic cell populations that are implicated in a wide range of higher-level neurobiological processes, most fundamentally the support of wake and cortical rhythms associated with cognition. Impairment of BFmc circuitry is linked with a host of neuropsychiatric and neurodegenerative (e.g., Alzheimer's disease) conditions as well as the cognitive impairments of normal aging. There is a fundamental gap however in understanding the cellular and synaptic circuit basis by which the BFmc support wakefulness and fast cortical rhythms associated with cognition. The long-term goal is to understand the functional circuit basis by which the BFmc supports cortical arousal. Our work during the prior grant period has revealed an unexpected and especially critical role for GABAergic BFmc neurons in promoting arousal and fast cortical rhythms. The objective in this particular application is to extend these findings by defining the functional, synaptic neurocircuit basis by which BFmc GABAergic neurons promote arousal and fast cortical rhythms associated with cognition. The central hypothesis is that BFmc GABAergic neurons promote arousal either indirectly through disinhibition of local GABAergic neurons in the posterior hypothalamus and/or directly via basocortical projections and, moreover, that the activity of these neurons in vivo is critically dependent upon excitatory inputs from the pontine parabrachial nucleus. The rationale for the proposed research is that identifying the circuit basis, including input and output relationships, by which BFmc GABAergic neurons support wakefulness/cortical arousal represents a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with arousal-based disorders. Guided by strong preliminary data, our hypotheses will be tested by pursuing three specific aims: 1) Determine if BFmc GABAergic neurons promote arousal by disinhibiting wake-promoting, cortically-projecting posterior lateral hypothalamic (pLH) neurons through local GABAergic interneurons; 2) Determine if BFmc GABAergic neurons promote arousal by directly inhibiting prefrontal cortex neurons; and 3) Determine if the ability of BFmc GABAergic neurons to support wake is critically dependent upon excitatory inputs from the pontine parabrachial nucleus. The approach is intellectually and technically innovative because it represents a new and substantive departure from contemporary models of BFmc function - which have emphasized cholinergic BFmc neurons in these processes - and because it employs a novel combination of newly developed and validated approaches, including complimentary in vivo and in vitro chemico- and opto-genetic 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 BFmc GABAergic regulation of arousal. Ultimately, such knowledge has the potential to inform the development therapeutic and interventional strategies for a host of neuropsychiatric, neurodegenerative and arousal-based disorders, including coma.
The proposed research is relevant to public health because understanding the synaptic and cellular mechanisms by which basal forebrain circuitry supports wakefulness is ultimately expected to increase understanding of how wakefulness and associated electrographic 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 burdens of human disability, in not only arousal-based disorders such as coma, but also in a host of neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia and the cognitive impairments of normal aging.
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