# Hippocampal memory mechanisms in nicotine relapse

> **NIH NIH K01** · UNIVERSITY OF CHICAGO · 2024 · $136,350

## Abstract

PROJECT SUMMARY/ABSTRACT
Cigarette smoking and nicotine dependence account for more than 7 million deaths per year worldwide. A major
challenge for treatments targeting smoking cessation is relapse: Most people who attempt to quit return to
smoking within months. When individuals stop smoking, being in environments where they used to smoke, like
bars, coffee shops, or bus stops, can trigger cravings for nicotine and lead to a return to smoking. This is known
as context-induced relapse, where context refers to the physical space or social setting associated with drug
use. These associative memories between contexts and nicotine are thought to be formed and retrieved by the
hippocampus and dependent on nicotinic acetylcholine receptors (nAChRs), specifically β2 containing-nAChRs
(β2*-nAChRs). However, the specific neuronal mechanisms underlying these nicotine-context associations in
the hippocampus and their modulation by β2*-nAChRs are not yet fully understood. Studying the involvement of
the hippocampus in learning these associations presents challenges, as it requires tracking the activity of the
same neurons over extended periods of time (days to weeks). To address this, I propose to use large-scale
imaging techniques that allow for long-term recording of neural activity in awake and behaving mice, combined
with computational tools to uncover the underlying neural dynamics. My central hypotheses are 1) that the
formation of nicotine-context memories in the hippocampus requires the binding of nicotine to β2*-nAChRs 2)
this binding, also enables hippocampal neurons to form stable memory representations of the nicotine-context
with repeated learning and 3) that stable memory traces are re-activated during context re-exposure leading to
relapse. To test these hypotheses, I will combine a novel behavior paradigm to assess context-induced relapse
behavior using virtual-reality in mice with two-photon imaging of large populations of hippocampal neurons. With
this technique, I will track activity of the same neurons during nicotine-context learning and memory retrieval.
Further, I will integrate this activity imaging with genetic techniques and pharmacological manipulations to
causally examine the role of β2*-nAChRs. Through this comprehensive approach, my research aims to provide
a detailed understanding of how nicotine-driven memory representations in the hippocampus contribute to
context-induced relapse, at a spatial and temporal scale that has not been achieved before. This mechanistic
understanding of neural computations in the hippocampus will potentially help identify novel therapeutics and
relapse-prevention strategies. To achieve these goals, I will receive mentorship and support from a group of
experts in various fields, including hippocampal memory processes (Dr. Mark Sheffield), nicotinic receptor
function (Dr. Daniel McGehee), task design and animal behavior (Dr. Rick Bevins), genetic techniques (Dr. Xiaoxi
Zhuang) and computational analys...

## Key facts

- **NIH application ID:** 10948539
- **Project number:** 1K01DA060994-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Seetha Lakshmi Krishnan
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $136,350
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948539

## Citation

> US National Institutes of Health, RePORTER application 10948539, Hippocampal memory mechanisms in nicotine relapse (1K01DA060994-01). Retrieved via AI Analytics 2026-07-20 from https://api.ai-analytics.org/grant/nih/10948539. Licensed CC0.

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