# Nicotine & Nodose: A Neural Basis for Peripheral Control over Nicotine Intake

> **NIH NIH F32** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $76,756

## Abstract

ABSTRACT
Nicotine addiction in the form of habitual tobacco use is the leading cause of premature death in the United
States and costs at least $170 billion in healthcare-related expenses each year. In addition to its addictive
qualities, nicotine triggers a plethora of respiratory, cardiovascular, gastrointestinal, and immune disorders,
reflecting its actions in not only the brain, but also in the body of smokers. While it is well established that the
addictive properties of nicotine are related to its direct pharmacological actions on nicotinic acetylcholine
receptors located in reward and motivation brain circuits, evidence from our lab suggests that noxious effects of
nicotine related to its actions on hindbrain aversion circuits (e.g. nucleus of the solitary tract (NTS),
interpeduncular nucleus, and medial habenula) play a significant role in regulating nicotine intake as well.
However, it is unclear if nicotine acts solely on these circuits by direct action on centrally expressed nicotinic
receptors or if nicotine also acts indirectly via vagally (nodose ganglia, NG) derived sensory inputs that terminate
primarily at the NTS. Preliminary data presented in this grant application strongly suggest a role for peripheral
actions of nicotine in controlling nicotine intake. For instance, the peripherally-restricted, full nicotine agonist,
methylnicotinium causes a conditioned place aversion beyond that generated by an equimolar dose of nicotine.
Further, the peripherally-restricted cholecystokinin receptor (CCKR) agonist, CCK-8 (10 µ*kg-1) decreased
volitional nicotine intake, especially at anxiogenic nicotine doses. Given these preliminary data and the
observation that plasma CCK levels are dysregulated by nicotine in rodents and humans, I hypothesize that
CCKRs in gut-innervating NG neurons potentiate aversive nicotine signals from the periphery to the NTS thereby
regulating nicotine intake. I will test this hypothesis using a nicotine intravenous self-administration mouse model
in combination with CCKR-specific lesions of the NG, FosTRAP mice, and chemogenetics. I will then define the
transcriptional responsiveness of the NG to an aversive dose of nicotine using single cell RNA sequencing.
Finally, I will employ an in vivo CRISPR-Cas9-mediated genomic cleavage strategy to knockdown prioritized
nicotine-response genes in the NG and assess the consequences on nicotine intake. Completion of this highly
innovative proposal will substantially advance my technical skills in mouse genetics, surgery, and computer
programing, and provide me with entirely new training in single cell sequencing, bioinformatics, and advanced
genome editing technologies. It will also contribute to the currently sparse literature about how sensory
information related to nicotine actions in the periphery are transmitted via the vagus to the hindbrain. Defining
such a mechanism will position me for a successful independent career in the exciting and rapidly growing field
of br...

## Key facts

- **NIH application ID:** 10866435
- **Project number:** 5F32DA054802-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kevin Braunscheidel
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,756
- **Award type:** 5
- **Project period:** 2022-07-06 → 2025-07-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866435

## Citation

> US National Institutes of Health, RePORTER application 10866435, Nicotine & Nodose: A Neural Basis for Peripheral Control over Nicotine Intake (5F32DA054802-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10866435. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*