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Dissecting the role of thalamic withdrawal-encoding ensembles in opioid use disorder

Award Number: R01DA064823
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Dissecting the role of thalamic withdrawal-encoding ensembles in opioid use disorder - PROJECT SUMMARY Opioid use disorder (OUD) is a major public health crisis, characterized by high relapse rates and limited long- term treatment success. When opioid use is discontinued, severe emotional and physical withdrawal symptoms emerge, creating an aversive state that persists beyond the acute withdrawal phase. As a result, opioids use becomes a means of alleviating withdrawal distress, making withdrawal a powerful driver of craving and relapse, even after prolonged abstinence. While pharmacological and behavioral treatments can mitigate withdrawal symptoms and reduce opioid use, they often fail to prevent long-term relapse. Therefore, understanding the neuronal circuits underlying withdrawal may help identify therapeutic targets to disrupt the withdrawal-relapse cycle that perpetuates OUD. Using a heroin self-administration model, our preliminary data identify the paraventricular thalamus (PVT) as a critical hub where withdrawal and seeking processes converge. We found that distinct subsets of PVT neurons activated during either spontaneous or naloxone-precipitated withdrawal are necessary for cued heroin seeking. Therefore, this proposal will systematically compare the circuit mechanisms engaged by PVT ensembles encoding these distinct, clinically relevant, withdrawal experiences to improve our mechanistic insight and inform targeted interventions. We will employ viral TRAP (Targeted Recombination in Active Populations) technology to gain genetic access to neurons activated during either spontaneous or precipitated withdrawal. To dissect circuit dynamics, we will use a multilevel, circuit-based approach integrating ex vivo electrophysiology, optogenetics, in vivo calcium imaging, and fiberphotometry. In Aim 1, we will characterize the real-time activity dynamics of PVT neurons encoding spontaneous versus precipitated withdrawal during the cue-induced heroin seeking test using in vivo calcium imaging. We will then determine the necessity of these distinct ensembles to heroin seeking by using temporally precise optogenetic inhibition specifically during cue presentation. In Aim 2, we will investigate pre- and post-synaptic plasticity in withdrawal-encoding PVT neurons by examining excitatory inputs from the prelimbic cortex (PL) and ventral subiculum (vSub). Next, we will assess synaptic adaptations in nucleus accumbens (NAc) D1- and D2-medium spiny neurons (MSNs) receiving inputs from these ensembles. Finally, in Aim 3, we will determine how the Dynorphin (Dyn)/Kappa Opioid Receptor (KOR) system dynamically regulates the activity of PVT withdrawal- encoding ensembles during the cued heroin seeking test. Using the novel kLight1.3 sensor, we will track local endogenous Dyn release onto withdrawal-encoding neurons while monitoring calcium dynamics with dual-color fiberphotometry. By elucidating the potentially state-dependent synaptic plasticity and neuromodulatory mechanisms that shape the activity of PVT withdrawal-encoding neurons, this study will uncover cellular and circuit-level processes sustaining the withdrawal-seeking cycle in OUD, thereby revealing novel targets for therapeutic intervention.


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 = $604,683 )
2026	2026	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Drug Use and Addiction Research Programs	000	1	8/3/2026	NEW	$604,683
														Subtotal = $604,683

Grand Total All Awards = $604,683

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Dissecting the role of thalamic withdrawal-encoding ensembles in opioid use disorder

Award Number: R01DA064823

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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