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Tracking and regulation of nicotine dependence in the insular cortex

Award Number: F30DA057823
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Tracking and regulation of nicotine dependence in the insular cortex - Project Summary The central goal of this proposal is to characterize the role of the insular cortex (InsCtx) in encoding and shaping the physiological drive to consume nicotine in nicotine-dependent mice. The InsCtx integrates sensory, visceral, and limbic information and is implicated in interoception: the sensing of internal bodily states. Interoception plays a crucial role in the development of addiction because the rewarding effects of addictive drugs and the aversive aspects of withdrawal are largely experienced as bodily sensations. Functional imaging in human smokers shows that InsCtx responses to smoking-related cues increase with self- reported craving intensity and with the expectancy of receiving nicotine. Intriguingly, after strokes involving the InsCtx, smokers report increased rates of smoking cessation and fewer nicotine cravings. Nevertheless, it remains unclear how the InsCtx encodes nicotine-replete and withdrawal states during the development of nicotine dependence, and if targeted InsCtx manipulations can curb cued nicotine-seeking behaviors. This gap in understanding is due in part to our inability to track the activity of large numbers of neurons throughout the development of dependence on and withdrawal from nicotine (or other addictive drugs). I have overcome this challenge by adapting our lab’s conceptual and technical framework for chronic two-photon calcium imaging of hundreds of InsCtx neurons during shifts in hunger/thirst to investigate InsCtx encoding of nicotine states and nicotine-predicting cues. Specifically, I propose to track InsCtx neurons as mice (i) develop nicotine dependence via home-cage drinking water exposure, and (ii) learn to respond to visual cues in order to receive oral nicotine rewards. In Aim 1, I will test the hypothesis that as an animal becomes dependent on nicotine, the pattern of InsCtx ongoing activity encoding states of satiety will change across days to reflect this new bodily state. Because nicotine has direct effects centrally on the brain as well as peripherally on bodily physiology, I will use natural and pharmacological manipulations to determine if ongoing InsCtx activity patterns reflect the central and/or peripheral actions of nicotine. In Aim 2, I will examine how InsCtx responses to nicotine- predicting cues correlate with concurrent recordings of mesolimbic dopamine release in the nucleus accumbens, which is known to mediate some of the rewarding aspects of addictive drugs and is profoundly altered in states of addiction. I will then test the hypothesis that acute optogenetic silencing of the InsCtx will disrupt learned dopaminergic and behavioral responses to nicotine-predicting cues. These experiments will advance our understanding of how InsCtx activity patterns change during the emergence of nicotine dependence, and will define the role of the InsCtx in drug-seeking behaviors. This work will improve our understanding of how exposure to nicotine modifies the neural representations associated with ‘physiological satiety’ during the development of drug dependence, and may help establish a basis for novel manipulations of insular cortex activity that achieve reductions in drug-seeking behaviors in patients with nicotine use disorders.


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: 2025 ( Subtotal = $53,974 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	3/18/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	2	3/6/2024	NON-COMPETING CONTINUATION	$52,694
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	5/2/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $40,041 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	1	2/17/2023	NEW	$0
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	2/17/2023	NEW	$40,041
														Subtotal = $40,041

Grand Total All Awards = $147,989

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Tracking and regulation of nicotine dependence in the insular cortex

Award Number: F30DA057823

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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