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Thalamostriatal Circuitry in Opioid Seeking

Award Number: R01DA054271
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Thalamostriatal Circuitry in Opioid Seeking - SUMMARY/ABSTRACT Reward-associated cues are unlikely to provoke reward seeking when that behavior is inappropriate, yet cues elicit opioid seeking in patients with opioid use disorder (OUD) when that behavior is unproductive or maladaptive. There is little understanding of how brain systems that can normally suppress unproductive reward seeking are modified by opioid use and causally contribute to opioid seeking. This is in part due to technical feasibility, as measuring adaptations in single neurons across the onset, maintenance, and relapse phases of opioid use is challenging. Here, I overcome this issue using a novel assay developed in my lab, wherein I longitudinally track activity in precisely defined neurons throughout heroin self-administration, extinction, and reinstatement using two-photon calcium imaging in head-restrained mice. We test the overarching hypothesis that a thalamostriatal subcircuit is inhibited by opioid use and by the presentation of stimuli that initiate opioid- seeking behaviors. In support of this hypothesis, my preliminary data suggest that posterior paraventricular thalamic neurons that project to the nucleus accumbens (pPVT NAc) become hypoactive and hypoexcitable as a result of repeated heroin use and display rapid reductions in activity during cue- and drug-induced reinstatement of heroin seeking. Furthermore, I show that optogenetically mimicking this inhibition during extinction initiates heroin seeking. To test my specific hypotheses, in Aim 1, I will longitudinally track the activity dynamics of single pPVT NAc neurons and neuronal ensembles throughout heroin self-administration, extinction, and reinstatement. In Aim 2, I will evaluate the long-lasting intrinsic and synaptic adaptations among pPVT NAc neurons at multiple timepoints following heroin self-administration. In Aim 3, I will determine the function of pPVT NAc neuronal activity for the suppression of heroin seeking during extinction, and expression of heroin seeking during reinstatement. Overall, this project will identify how a brain circuit that inhibits reward seeking in inappropriate conditions is modified by opioid use and causally influences opioid-seeking behavior.


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 = $339,750 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	5	2/11/2026	NON-COMPETING CONTINUATION	$339,750
														Subtotal = $339,750

Issue Date FY: 2025 ( Subtotal = $339,750 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	4	3/3/2025	NON-COMPETING CONTINUATION	$305,775
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	001	4	4/9/2025	NON-COMPETING CONTINUATION	$33,975
														Subtotal = $339,750

Issue Date FY: 2024 ( Subtotal = $339,750 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	3	1/16/2024	NON-COMPETING CONTINUATION	$305,775
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	001	3	4/24/2024	NON-COMPETING CONTINUATION	$33,975
														Subtotal = $339,750

Issue Date FY: 2023 ( Subtotal = $339,750 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	2	1/23/2023	NON-COMPETING CONTINUATION	$339,750
														Subtotal = $339,750

Issue Date FY: 2022 ( Subtotal = $339,469 )
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	3/11/2022	NEW	$339,469
														Subtotal = $339,469

Grand Total All Awards = $1,698,469

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Thalamostriatal Circuitry in Opioid Seeking

Award Number: R01DA054271

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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