Wednesday, August 20, 2025 8/20/2025

Circuit-Selective Astroglial Plasticity During Opioid Relapse

Award Number: K01DA054339
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Circuit-Selective Astroglial Plasticity During Opioid Relapse - Abstract Vulnerability to relapse despite prolonged abstinence is a principal feature of drug addiction. Decades of research have expanded our understanding of the neural basis of relapse, but have yielded few effective treatments that restore top-down control over drug seeking in active and former users. In animal models, repeated drug use, but not repeated exposure to natural rewards, results in excess glutamate transmission within corticofugal projections to the striatum in the presence of reward-associated cues and contexts that drive seeking. This behavioral paradigm has been used to model neural adaptations that trigger relapse, since reactivity to drug-related cues is linked to drug craving in humans. The dysregulation of glutamate transmission after chronic heroin use arises in part from enduring changes in peripheral astrocyte processes that insulate active synapses and express the glutamate transporter GLT-1, consistent with a growing literature that illustrates a prominent role for this cell type in maintaining the integrity of excitatory synaptic transmission. My published data show that astrocytes in the NAcore undergo profound transient morphological plasticity in response to drug- but not sucrose-conditioned cues and that this plasticity serves to attenuate seeking behavior. Heroin-associated cues also stimulate an increase in surface-proximity of GLT-1 on the astroglial membrane, an adaptation expected to limit glutamate spillover during relapse in preclinical models. The goal of this proposal is to explore whether measures of astroglial plasticity that I have discovered are linked to transmitter release from cortical projections within the NAcore and to uncover intracellular signaling events that trigger morphological plasticity in astrocytes during drug-seeking. A final goal of this proposal is to determine whether cue-induced astrocyte adaptations impact different post-synaptic targets, since the two principle neuronal subtypes in the NAcore, D1- and D2-MSNs differentially impact drug seeking behavior. In Aim 1, I will combine confocal microscopy with in vivo fiber photometry in order to identify the time course of astroglial plasticity during a 2-hr reinstatement session. In Aim 2, I will pair optogenetics with confocal microscopy to determine whether glutamate from prelimbic cortical terminals is necessary to drive astrocyte motility and GLT-1 surface diffusion after extinction from heroin self-administration. In Aim 3, I will interfere with the signaling cascade that drives astrocyte process motility during seeking using viral-mediated delivery of shRNAs selectively in astrocytes. Finally, in Aim 4 I will use confocal microscopy in transgenic D1- and D2-Cre rats to determine whether astrocyte processes or surface- proximal GLT-1 are selectively associated with D1- or D2-MSNs during cue-reinstated seeking. These Aims will provide me with comprehensive training in optogenetics as well as with viral tools that will allow me to selectively manipulate protein expression in astrocytes and will link my previous findings with the underlying neural circuitry. The relevance of this work extends beyond relapse to opioids and may have implications for normal synaptic physiology underlying motivated 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: 2025 ( Subtotal = $183,546 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Drug Use and Addiction Research Programs	002	4	7/2/2025	NON-COMPETING CONTINUATION	$183,546
2025	2023	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Drug Use and Addiction Research Programs	001	2	2/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$120,508
2025	2022	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	2/14/2025	NEW	-$120,508
														Subtotal = $183,546

Issue Date FY: 2024 ( Subtotal = $179,096 )
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Drug Use and Addiction Research Programs	001	3	7/23/2024	NON-COMPETING CONTINUATION	$179,096
2024	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Drug Use and Addiction Research Programs	000	2	11/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $179,096

Issue Date FY: 2023 ( Subtotal = $179,096 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Drug Use and Addiction Research Programs	001	2	8/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$179,096
2023	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	8/8/2023	NEW	$0
														Subtotal = $179,096

Issue Date FY: 2022 ( Subtotal = $192,802 )
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	7/13/2022	NEW	$192,802
														Subtotal = $192,802

Grand Total All Awards = $734,540

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Circuit-Selective Astroglial Plasticity During Opioid Relapse

Award Number: K01DA054339

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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