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Hippocampal memory mechanisms in nicotine relapse

Award Number: K01DA060994
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Hippocampal memory mechanisms in nicotine relapse - 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 analysis of large-scale neural recordings (Dr. Jason MacLean). This mentored training will facilitate my transition to become an independently funded investigator, where I will continue to study the neurobiological mechanisms underlying drug-dependence and relapse.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $163,117 )
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	3	5/19/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$163,117
2026	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	000	2	5/15/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	002	2	6/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $163,117

Issue Date FY: 2025 ( Subtotal = $135,054 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	000	2	6/23/2025	NON-COMPETING CONTINUATION	$135,054
														Subtotal = $135,054

Issue Date FY: 2024 ( Subtotal = $136,350 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	000	1	5/20/2024	NEW	$136,350
														Subtotal = $136,350

Grand Total All Awards = $434,521

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Hippocampal memory mechanisms in nicotine relapse

Award Number: K01DA060994

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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