Date of Award

Fall 9-30-2022

Embargo Period

9-30-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

James Otis, PhD

Abstract

Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behaviors and opioid use disorder (OUD). Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. Here, we investigate the posterior paraventricular thalamus (pPVT) as a behavioral mediator due to its strong connectivity with brain structures important for reward processing, such as the nucleus accumbens (NAc). We and others have found pPVT-NAc neuronal activity is inhibited during reward seeking, but activated when such behaviors would be inappropriate, such as during stress or satiety. However, it is unclear whether pPVT-NAc activity is necessary and sufficient for the suppression reward seeking, and whether opioid use modifies this circuit’s role in motivated behaviors. To investigate this, we first developed a head-restrained operant self-administration paradigm to use in combination with in vivo two-photon calcium imaging. Using this strategy, we identified pPVT-NAc neuronal ensembles that are inhibited upon sucrose self-administration and seeking, but are tonically active when this behavior is suppressed. Subsequent electrophysiological, optogenetic, and chemogenetic experiments revealed that pPVT-NAc neurons innervate accumbal parvalbumin interneurons (PV-INs) through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking. However, acute opioid injections rapidly dysregulated pPVT-NAc ensemble dynamics, weakened pPVT-NAc innervation of downstream neurons, and unleashed reward seeking in a manner that dependent on pPVT µ-opioid receptors. To further investigate this opioid-induced pPVT-NAc plasticity, we next paired chronic heroin self-administration with two-photon calcium imaging, and found that activity in pPVT-NAc neurons is profoundly reduced during heroin use and seeking. Ensuing electrophysiological experiments demonstrated long-lasting adaptations at pPVT-NAc to PV-IN synapses, an effect that functionally disinhibits heroin seeking. Finally, selective restoration of activity at pPVT-NAc to PV-IN synapses abolished cue-, drug-, and stress-triggered relapse. Together, these findings reveal a thalamo-accumbal to PV-IN circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids, though restoration of this circuit following chronic heroin encourages behavioral inhibition and prevents relapse in OUD.

Rights

Copyright is held by the author. All rights reserved.

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