# Genetic modifiers of Chrna5 deletion in mice: role in nicotine behaviors modulated by the medial habenula-IPN pathway

> **NIH NIH U01** · UNIVERSITY OF COLORADO · 2020 · $714,690

## Abstract

PROJECT SUMMARY/ABSTRACT
Less than 1 in 10 individuals who attempt to quit smoking remain abstinent for 1 year. This poor quit rate is
driven, in part, by the fact that currently available drugs used to aid in smoking cessation are only moderately
effective, at best. Thus, there is a great need to develop novel drugs that are more effective for smoking
cessation. It is the goal of this project to use a novel genetic strategy to identify new biological targets for the
potential development of novel smoking cessation drugs. The genetic strategy is based upon identifying
modifier genes that alter nicotine responses in mice that have a null mutation in Chrna5, the gene that codes
for the nicotinic receptor α5 subunit. In effect, modifier genes are genes that contribute to physiological and/or
molecular processes that are important for the behavior of interest but that generally go undetected in the
absence of a perturbation in the gene that they modify. Because variants in Chrna5 alter risk for nicotine
dependence in humans and studies in rodents clearly demonstrate that Chrna5 is critical for many nicotine-
related behaviors, we believe that identifying genes that modify the effect of Chrna5 deletion on nicotine
behaviors will uncover new genes relevant to nicotine dependence that may serve as novel targets for novel
smoking cessation pharmacotherapies. Importantly, the behaviors that we plan to screen for modifiers are not
only dependent upon Chrna5, but also dependent uponthe medial habenula-IPN pathway, a neural pathway
that is thought to play a critical role in nicotine dependence. To identify genetic modifiers of the effect of
Chrna5 deletion on nicotine behaviors, we propose 3 aims. In specific aim 1, we will breed the Chrna5 null
mutation onto each of the B6-ChrA/J chromosome substitution strains (CSS) and identify chromosomes that
harbor modifier genes for the effect of Chrna5 deletion on three nicotine behaviors, oral nicotine intake,
somatic signs of nicotine withdrawal, and nicotine conditioned place preference. For specific aim 2, we will
fine map those chromosomes that harbor modifier genes using sequential congenic strains. Typically, 3
generations of congenic strains starting from a CSS strain provides mapping resolution equivalent to that of
any high resolution mapping population. Finally, in specific aim 3, we will use RNA-seq to identify genes
whose expression is altered by the identified modifier genes. Importantly, we will use a state of the art genetic
strategy that will allow us to examine gene expression in a neural cell population that is highly relevant to the
behaviors: Chrna5 expressing cells of the interpeduncular nucleus. By combining the results of this aim with
modifier loci identified through aims 1 and 2, we expect to narrow the list of potential candidate modifier genes
and identify pathways specifically impacted by the modifier genes. In short, we believe that this strategy will
lead to the identification of previo...

## Key facts

- **NIH application ID:** 9838219
- **Project number:** 5U01DA043802-03
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** RICHARD A RADCLIFFE
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $714,690
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838219

## Citation

> US National Institutes of Health, RePORTER application 9838219, Genetic modifiers of Chrna5 deletion in mice: role in nicotine behaviors modulated by the medial habenula-IPN pathway (5U01DA043802-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838219. Licensed CC0.

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