# The direct regulation of feeding-driving hypothalamic GABAergic neurons on stress responses

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $195,000

## Abstract

Project Summary
To develop effective therapies against the stress-related mental disorders (i.e., PTSD), it is highly important to
fully understand neural basis and mechanisms that underlie stress responses. The properly orchestrated
activity dynamics of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of
hypothalamus (PVH, denoted as PVHCRH neurons), the apex of the hypothalamic-pituitary-adrenal (HPA) axis,
are very important for underlying normal stress responses. PVHCRH neuronal activity is well known to be closely
controlled by a complex of stimulatory and inhibitory actions imposed by upstream GABAergic and
glutamatergic inputs as well as other hormonal and synaptic inputs. Despite the stress responses are well
understood at the level of PVHCRH neurons, very little is known about how stress signals are directly triggered,
buffered and regulated by upstream neurons that send direct inputs to PVHCRH neurons. Our pilot study
showed that arcuate nucleus (Arc) GABAergic neurons (denoted as ArcGABA neurons) represent one major
presynaptic GABAergic source of PVHCRH neurons (Notably, the AgRP subset of ArcGABA neurons has been
shown DO NOT sending direct inputs to PVHCRH neurons). Our preliminary tests further found that ArcGABA
neurons a) inversely regulate PVHCRH neuronal activity in a time-locked manner, b) respond in a stark contrast
phase with PVHCRH neurons but in the same phase with GABA release onto PVHCRH neurons in response to
the same stressor, and c) drive stress level in an opposite direction to PVHCRH neurons. Based on these
compelling findings, we hypothesize that feeding-driving ArcGABAergic neurons are the anatomical and functional
upstream of PVHCRH to directly . To test this hypothesis, the combination of
in vivo fiber photometry, fluorescent intensity-based neurotransmitter sensors, RetroLEAP (retrograde
transsynaptic Labelling, Expression And Perturbation), intersectional Cre-loxP/FRT-FlpO genetic approaches
neurons
regulate stress responses
and the ethologically relevant behavioral
tests
will be used in this proposal. Specifically, we will test whether
inputs from ArcGABA neurons directly drive PVHCRH
vivo activity changes in ArcGABA neurons directly shape
balance
between
feeding
behaviors and stress
responses to stressor 
 the PVHCRH-HPA axis responsivity
responses in animals exposed to
(Aim1). We will also test whether in
and regulate
predator stress while
 the
foraging
for
food
(Aim 2). The expected findings will functionally bridge feeding-driving ArcGABA neurons with stress-
responsive PVHCRH neurons, thereby providing significant information to understand a novel brain mechanism
underlying the integrative control of adaptive feeding behaviors and stress responses.

## Key facts

- **NIH application ID:** 10807642
- **Project number:** 1R21MH133228-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Yuanzhong Xu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,000
- **Award type:** 1
- **Project period:** 2023-12-08 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807642

## Citation

> US National Institutes of Health, RePORTER application 10807642, The direct regulation of feeding-driving hypothalamic GABAergic neurons on stress responses (1R21MH133228-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10807642. Licensed CC0.

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