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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073613-08
Application #
9405043
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
He, Janet
Project Start
2011-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Venner, Anne; Anaclet, Christelle; Broadhurst, Rebecca Y et al. (2016) A Novel Population of Wake-Promoting GABAergic Neurons in the Ventral Lateral Hypothalamus. Curr Biol 26:2137-43
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Qiu, Mei Hong; Chen, Michael C; Fuller, Patrick M et al. (2016) Stimulation of the Pontine Parabrachial Nucleus Promotes Wakefulness via Extra-thalamic Forebrain Circuit Nodes. Curr Biol 26:2301-12
Yazaki-Sugiyama, Yoko; Yanagihara, Shin; Fuller, Patrick M et al. (2015) Acute inhibition of a cortical motor area impairs vocal control in singing zebra finches. Eur J Neurosci 41:97-108

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