# Decoding brain circuit underlying metabolic regulation of sleep-wake behavior

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $124,577

## Abstract

Contact PD/PI: Cui, Huxing
Project Summary / Abstract
Sleep disorders and obesity are inextricably linked – poor sleep quality and short sleep duration increase the
risk of developing obesity, while obesity is an independent risk factor for chronic sleep disruption (CSD) and
excessive daytime sleepiness (EDS). Despite a clear bidirectional and pernicious association between obesity
and sleep disorders, the neural substrates mediating this association remain largely unknown. Our research
program seeks to identify critical neural circuit linking metabolic alterations to CSD and EDS. Our long-term
goal is to delineate the neural circuits underlying metabolic regulation of sleep-wake behavior. We have
recently found that adipocyte-derived metabolic hormone, leptin, promotes wakefulness and chemogenetic
activation of a subset of GABAergic neurons in the lateral hypothalamic area (LHA) expressing leptin receptor
(LepR) completely disrupts sleep in mice. The overall objective of this research proposal is to clarify how leptin
acts on key hypothalamic neurons to affect normal sleep-wake cycle. Build upon strong preliminary data, the
central hypothesis is that circulating leptin acts on a subset of LHA LepR-expressing GABAergic neurons to
affect sleep-wake behavior through their projections to the ventral tegmental area (VTA) and/or preoptic area
(POA) and thereby contribute to CSD and EDS commonly associated with obesity. We will test our hypothesis
by pursuing following two specific aims: 1) determine if the LHA is a key site mediating the action of leptin on
sleep-wake regulation and 2) determine if leptin engages LHAVTA and/or LHAPOA circuits to regulate
sleep-wake behavior. Advanced neuroscience techniques will be employed to answer these questions,
including Cre/loxP technology, optogenetics/chemogenetics, in vivo fiber photometry, and electrophysiology
coupled with chronic wireless recording of EEG/EMG in freely moving animals. The proposed research is
significant because it is expected to not only advance and our understanding of hypothalamic regulation of
sleep-wake behavior but also shed light on largely unknown mechanisms that connect metabolic disorders to
sleep-wake regulation. The proposed research is also innovative because it utilizes a combination of state-of-
art neuroscience techniques coupled with sophisticated physiological measurements to address an important
yet largely under-investigated question – what are the underlying neural circuits mediating CSD and EDS in
obesity? Such knowledge may ultimately lead to the development of a novel strategy to effectively manage
sleep problems associated with obesity in human patients.
Project Summary/Abstract Page 6

## Key facts

- **NIH application ID:** 11459911
- **Project number:** 7R01HL153274-05
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Huxing Cui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $124,577
- **Award type:** 7
- **Project period:** 2001-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11459911

## Citation

> US National Institutes of Health, RePORTER application 11459911, Decoding brain circuit underlying metabolic regulation of sleep-wake behavior (7R01HL153274-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11459911. Licensed CC0.

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