Date of Award

2020

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Peter W. Kalivas

Second Advisor

Thomas C. Jhou

Third Advisor

Jeffery Jones

Fourth Advisor

Leszek Kaczmarek

Fifth Advisor

Carmela Reichel

Sixth Advisor

Michael Scofield

Abstract

To date, heroin abuse is a leading cause of drug overdose-related deaths in the United States, highlighting a need for further research elucidating effects of maladaptive neuroadaptations following prolonged heroin use. Activation of the tetrapartite synapse in nucleus accumbens core (NAcore), which comprises of pre- and post-synapse, astrocytic processes, and surrounding extracellular matrix (ECM), has been linked to increased relapse vulnerability. Specifically, degradation of ECM by activated matrix metalloproteinases (MMPs) is involved in extracellular synaptic remodeling both constitutively and transiently in extinguished and drug seeking conditions, respectively. Although increases in MMP-2,9 fluorescence can be localized to soma and dendritic processes of medium spiny neurons (MSNs) in NAcore, it is unknown which specific cell types of the tetrapartite synapse harbor changes in MMP activity under extinguished and cued reinstatement conditions (15min). I used a viral transfection strategy to label NAcore D1 and D2 MSNs and astrocytes in heroin self-administering rats, and measured localization of activated MMP-2,9 gelatinolytic puncta after FITC-gelatin microinjection under extinguished and reinstated conditions. Astrocytes exhibited reduced synaptic MMP activity co-localized with peripheral processes after extinction, but gelatinolytic activity was restored to control levels during cued heroin seeking. For D1 MSNs, I observed transient increases in MMP-9 activity localized around dendritic segments in reinstated animals compared to both saline controls and heroin-extinguished animals. D2 MSNs showed increased MMP-2 activity only in heroin-extinguished animals, but MMP-2,9 activity after 15 min reinstatement was transiently reduced to saline levels. In both cases, increased MMP activity was enhanced around dendritic spines compared to dendrite shaft. The observed changes in MMP activity around D1 and D2 MSNs during heroin seeking are transient and reversible as gelatinolytic puncta around both cell types returned to extinguished levels after 120min of heroin seeking. I also examined effects of home-cage abstinence and heroin refraining on MMP activity selectively around D1 and D2 MSNs. Finally, I studied involvement of tissue inhibitors of metalloproteinases (TIMPs) in NAcore during reinstatement to determine if local MMP inhibition around specific cell-types is necessary for cued heroin seeking. These findings reveal how NAcore ECM signaling underlying constitutive and transient synaptic plasticity relies in part on specific cell-types.

Rights

All rights reserved. Copyright is held by the author.

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