# Molecular-Genetic Dissection of Subcortical Circuitry Regulating Arousal

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $451,316

## Abstract

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-b...

## Key facts

- **NIH application ID:** 10530875
- **Project number:** 2R01NS073613-10A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Patrick M Fuller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $451,316
- **Award type:** 2
- **Project period:** 2011-02-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10530875

## Citation

> US National Institutes of Health, RePORTER application 10530875, Molecular-Genetic Dissection of Subcortical Circuitry Regulating Arousal (2R01NS073613-10A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10530875. Licensed CC0.

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