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Involvement of habenulo-interpeduncular circuitry in nicotine reward and aversion

Award Number: F32DA053797
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/20/2022
PERIOD OF PERFORMANCE END DATE: 01/19/2025

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Involvement of habenulo-interpeduncular circuitry in nicotine reward and aversion - Project Summary/Abstract Smoking tobacco is one of the leading causes of preventable mortality in adults worldwide. However, there is currently a lack of pharmacological smoking cessation aids and their efficacy is limited. Therefore, there is an urgent need to better understand the neural mechanisms that underlie nicotine addiction for the development of novel smoking cessation treatments. Much of our understanding of the reinforcing effects of nicotine are derived from studies focused on canonical mesolimbic dopamine reward circuitry in the brain. Research suggests that the habenulo-interpeduncular pathway consisting of the medial habenula (MHb) and interpeduncular nucleus (IPN) contributes to the aversive motivational properties of high nicotine doses. It is speculated that activation of nicotinic cholinergic receptors (nAChRs) stimulates excitatory acetylcholine/glutamate (ACh/Glu) co-releasing projection neurons which activate ɣ-aminobutyric acid (GABA) neurons in the IPN. However, silencing IPN neurons in rodent models has also been shown to reduce nicotine consumption and reward. Thus, it is possible that modulation of MHb→IPN circuit activity may contribute to the balance of nicotine reward and aversion, a critical component of nicotine addiction liability. However, it is unknown how MHb→IPN neurons respond to nicotine within the context of reward related behavior. It is also unclear whether nicotine-induced activation of this circuit is necessary to elicit nicotine’s aversive properties. In the proposed project, I aim to test the hypothesis that modulation of IPN GABAergic neuron activity by nicotine is critical for balancing nicotine reward/aversion. I also aim to test the hypothesis that nicotine-induced control of ACh/Glu projection neuron activity from the MHb to IPN controls nicotine reward/aversion balance. Thus, I will assess the influence of rewarding or aversive nicotine doses on MHb or IPN neural activity during the performance of conditioned place preference/conditioned place aversion (CPP/CPA) procedures using in vivo fiber photometry combined with genetically encoded calcium indicators (GCaMPs). Finally, I will use in vivo optogenetics to selectively activate or silence MHb or IPN neurons to investigate whether specific components of this circuit are sufficient to drive nicotine reward/aversion balance. The goal of this project is to provide a better understanding of circuit-specific mechanisms that may contribute to nicotine reward/aversion balance, which will aid in the development of precise pharmacological treatments for smoking cessation.


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 = -$857 )
2026	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	000	3	1/29/2026	NON-COMPETING CONTINUATION	-$857
														Subtotal = -$857

Issue Date FY: 2024 ( Subtotal = $81,364 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	000	3	1/26/2024	NON-COMPETING CONTINUATION	$76,052
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	001	3	5/1/2024	NON-COMPETING CONTINUATION	$5,312
														Subtotal = $81,364

Issue Date FY: 2023 ( Subtotal = $73,772 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	000	2	2/7/2023	NON-COMPETING CONTINUATION	$73,772
														Subtotal = $73,772

Issue Date FY: 2022 ( Subtotal = $69,802 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	000	1	1/20/2022	NEW	$68,562
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	003	1	5/23/2022	NEW	$6
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	002	1	4/21/2022	NEW	$1,234
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Drug Use and Addiction Research Programs	001	1	2/16/2022	NEW	$0
														Subtotal = $69,802

Grand Total All Awards = $224,081

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Involvement of habenulo-interpeduncular circuitry in nicotine reward and aversion

Award Number: F32DA053797

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/20/2022

PERIOD OF PERFORMANCE END DATE: 01/19/2025

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