# Identifying the contribution of a brainstem circuit to compulsive food seeking

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2024 · $74,284

## Abstract

PROJECT SUMMARY/ABSTRACT
 Obesity and eating disorders can present with uncontrolled and compulsive food seeking that is resistant
to negative consequences. The goal of this proposal is to understand how consequences of food seeking actions
are integrated into motivational neural circuits and describe how these circuits are modulated by homeostatic
state. The mesolimbic dopamine (DA) system and the ventral tegmental area (VTA) are implicated in the control
of compulsive food seeking behavior. Aversive stimuli can impact the DA system to reduce food seeking, but the
impact of this stimuli is blunted when animals are hungry. Homeostatic circuits, like those downstream of agouti-
related peptide (AGRP) expressing neurons, dampen aversive stimuli by suppressing neural activity in the
parabrachial nucleus (PBN). The PBN provides input to the VTA, indicating that hunger may modulate the ability
of aversive stimuli to impact DA signaling and compulsive behavior. I hypothesize that AGRP neurons inhibit the
response of VTA projecting PBN neurons to aversive stimuli, leading to continued food seeking despite negative
consequences. To test this hypothesis, I will use in vivo neuroimaging of VTA projecting PBN neurons during
aversive stimuli and neurobehavioral analysis of compulsive operant food seeking behavior. In specific Aim 1, I
will use microendoscopic calcium imaging to resolve the neural activity of individual VTA projecting PBN neurons
during footshock, and I will determine how this neural activity changes following stimulation of AGRP neurons.
In specific Aim 2, I will test the necessity of the PBN to VTA circuit in punishment-induced suppression of food
seeking. Additionally, I will test whether activation of AGRP neuron terminals in the PBN is sufficient to increase
food seeking despite negative consequences. Together, these experiments inform on how negative
consequences impact food seeking and how this can be modulated by homeostatic circuits. Understanding this
interaction will provide a novel perspective on compulsive behavior and will identify mechanisms for how
compulsive behavior can develop in disease states where homeostatic circuits are disrupted. Through
completing this proposal, I will gain valuable skills in in vivo neuroimaging and build my expertise in the study of
operant food seeking behavior. These skills will complement my prior expertise, and significantly improve my
ability to address the neural control of food-seeking behavior in my career. These technical skills, along with the
training in research, mentoring, and professional development are necessary to support my success in pursuit
of a career as an independent scientist studying the neurobiology of feeding.

## Key facts

- **NIH application ID:** 10923900
- **Project number:** 5F32DK135401-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nicholas K Smith
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923900

## Citation

> US National Institutes of Health, RePORTER application 10923900, Identifying the contribution of a brainstem circuit to compulsive food seeking (5F32DK135401-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10923900. Licensed CC0.

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