# Reward Signaling in the Gut-Brain Axis

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2022 · $17,800

## Abstract

PROJECT SUMMARY
Obesity is not only a leading cause of death in the US, but also a risk factor for nearly all other top causes of
death including heart disease, pulmonary disease, stroke, and cancer. Overconsumption of high-fat high-sugar
foods is a driver of obesity, but the mechanism for this is unclear. Nodose ganglia (NG) neurons of the vagus
nerve transmit post-ingestive signals for fats and sugars from the gut to the brain to regulate food intake and
reinforce food choice. Previous studies have demonstrated that vagal activity in response to post-ingestive
signals is reduced in obesity, which may lead to increased food intake. To understand how altered
macronutrient signaling may lead to obesity requires understanding its basic physiology, which has not been
fully elucidated. My preliminary data reveals distinct neuronal populations in the vagus nerve are required for
post-ingestive fat or sugar signaling, but whether these signals are sufficient to reinforce conditioned behavior
is unclear. I have previously shown that ablation of neurons expressing cholecystokinin receptor (CCKR)
affects fat- but not sugar-mediated satiation, indicating CCKR may be a specific marker for fat responsive
vagal afferent neurons. Accordingly, I hypothesize that fats and sugars activate phenotypically and
functionally distinct vagal ensembles in the gut-brain axis, which are sufficient to reinforce
conditioned behavior, and this activation is reduced in obesity. To address these hypotheses, we will use
FosTRAP mice, an activity-dependent genetic targeting model, to selectively target vagal sensory neurons that
respond to either fat or sugar. In aim 1, we will test whether optogenetic activation of fat or sugar sensing vagal
neurons is sufficient to trigger nigrostriatal dopamine release, and for animals to learn to self-stimulate, two
hallmarks of reward. In aim 2, we will test the necessity of CCK receptor expressing vagal sensory neurons in
fat, but not sugar reward, by performing a flavor-nutrient conditioning experiment with and without selective
ablation of vagal afferents expressing CCKR, using the conjugated neurotoxin CCK-Saporin. In aim 3, we will
test how high-fat high-sugar diet intake disrupts nutrient sensing by using FosTRAP mice to compare neural
responses to intragastric stimuli before and after the onset of obesity within the same animal. This work will for
the first time characterize nutrient-specific signaling in the gut-brain reward circuitry in lean and obese
conditions for future study and possible therapeutic targets.

## Key facts

- **NIH application ID:** 10464137
- **Project number:** 1F31DK132868-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Molly McDougle
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $17,800
- **Award type:** 1
- **Project period:** 2022-04-29 → 2022-06-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464137

## Citation

> US National Institutes of Health, RePORTER application 10464137, Reward Signaling in the Gut-Brain Axis (1F31DK132868-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464137. Licensed CC0.

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