# Dissection of a novel inhibitory hypothalamic arousal circuit

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $378,438

## Abstract

Project Summary/Abstract
Recent work by our laboratory has identified a delimited node of VGAT+ (GABAergic) neurons in the ventral
lateral hypothalamus (LHVGAT) that are both necessary and sufficient for normal behavioral and electroen-
cephalographic (EEG) wakefulness. There is a fundamental gap however in understanding the cellular and
synaptic circuit basis by which LHVGAT neurons trigger waking. The long-term goal is to understand the func-
tional circuit basis by which LHVGAT neurons generate and regulate behavioral and EEG arousal. The objective
in this particular application is to extend our previous findings by defining the functional, synaptic “neurocircuit”
basis by which LHVGAT neurons trigger wakefulness. The central hypothesis is that LHVGAT neurons promote
wake and fast EEG rhythms through direct inhibition of the sleep-active ventrolateral preoptic (VLPO) nucleus,
located within the greater preoptic area. The rationale for the proposed research is that identifying the circuit
basis by which LHVGAT neurons promote waking represents a critical first step towards manipulating them and
reducing the dysfunction experienced by individuals with arousal-based disorders, including hyperarousal-
driven insomnia. Guided by strong preliminary data, our hypotheses will be tested by pursuing three specific
aims: 1) determine if LHVGAT neurons promote arousal through direct inhibition of sleep-promoting VLPO neu-
rons; 2) define the functional synaptic physiology of the LHVGAT–VLPO interface, including the cellular profile of
the targeted neurons; and 3) determine synaptic inputs to the LHVGAT and establish a functional tri-synaptic cir-
cuit spanning inputLHVGATVLPO. The approach is intellectually and technically innovative because it rep-
resents a new and substantive departure from contemporary models of the role of LH neurons in wake-sleep
regulation and because it employs a novel combination of newly developed and validated approaches, includ-
ing complimentary in vivo and in vitro 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 LHVGAT regulation of wakefulness and fast cortical rhythms associated with cognition.
Ultimately, such knowledge has the potential to inform the development of therapeutic and interventional strat-
egies to reduce the dysfunction and negative health effects experienced by a growing number of patients
worldwide with arousal-based disorders and disorders of arousal and sleep, including hyperarousals of PTSD
and insomnia.

## Key facts

- **NIH application ID:** 9904769
- **Project number:** 5R01NS103161-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Patrick M Fuller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,438
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904769

## Citation

> US National Institutes of Health, RePORTER application 9904769, Dissection of a novel inhibitory hypothalamic arousal circuit (5R01NS103161-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904769. Licensed CC0.

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