# Regulation of arousal state by the suprachiasmatic clock

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $419,499

## Abstract

Project Summary
There is a fundamental gap in understanding the circuit, cellular and synaptic bases by which the circadian
pacemaker, located in the hypothalamic suprachiasmatic nucleus (SCN) of mammals, regulates brain arousal.
This knowledge gap is an important problem because it not only reduces our ability to treat arousal disorders,
such as hypersomnia and fatigue, but also impacts treatment and deeper understanding of many
neuropsychiatric, neurodegenerative and neurological disorders that often include severe arousal disruption,
including depression and Alzheimer's disease. Our long-term goal is to understand the anatomic, cellular and
synaptic outflow bases by which the SCN regulates brain arousal. The objectives of this application are to 1)
determine if Neuromedin S-producing SCN (SCNNMS) neurons promote arousal, 2) define their state-dependent
firing profile in vivo; 3) establish a functional tri-synaptic circuit spanning SCNNMS->dorsomedial hypothalamus
(DMH)->ventrolateral preoptic nucleus (VLPO), 4) define the functional synaptic physiology of the DMH->VLPO
interface, including the cellular profile of the targeted neurons, 5) determine presynaptic inputs to SCNNMS
neurons, and 6) define the molecular/transcriptional landscape of SCNNMS neurons. The central hypothesis is
that SCNNMS neuron are both necessary and sufficient for clock regulation of arousal levels. The rationale for
the proposed research is that identifying the anatomic, cellular and synaptic bases by which the SCN 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 four specific aims: 1) Determine in vivo if acute activation/inhibition of SCNNMS neurons can
promote/attenuate arousal, respectively, and, via in vivo Ca+2 imaging, if they exhibit a wake-active profile; 2)
Demonstrate that SCNNMS neurons are functionally, synaptically connected with sleep-promoting VLPO
neurons via a DMH `relay'; 3) Determine the sources of presynaptic inputs to SCNNMS neurons and confirm
functional connectivity; and 4) Determine molecular heterogeneity within the SCNNMS cell population. The
approach is intellectually and technically innovative because it seeks to reveal the mechanistic basis by which
the SCN regulates brain arousal and because it employs a novel combination of newly developed and
validated approaches. The proposed research is significant, because it is expected to vertically advance and
expand understanding of the cellular and synaptic mechanisms subserving the SCN clock. Ultimately, such
knowledge has the potential to inform the development of treatments to reduce the dysfunction and negative
health effects experienced by not only the growing number of patients with circadian- and arousal-based
disorders, such as hypersomnia and fatigue, but also of those suffering one of the host of n...

## Key facts

- **NIH application ID:** 10457494
- **Project number:** 5R01NS118856-02
- **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:** $419,499
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457494

## Citation

> US National Institutes of Health, RePORTER application 10457494, Regulation of arousal state by the suprachiasmatic clock (5R01NS118856-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10457494. Licensed CC0.

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