Date of Award

2022

Embargo Period

7-28-2022

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Christopher Cowan

Second Advisor

John Woodward

Third Advisor

Stephen Duncan

Fourth Advisor

Tom Jhou

Fifth Advisor

Catrina Robinson

Abstract

Re-exposure to diffuse and discrete cues associated with active drug use can trigger relapse in individuals recovering from substance use disorder (SUD). Relapse-like behavior is promoted in the nucleus accumbens (NAc) by the preponderant activation of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), while it is generally impeded by D2 dopamine receptor-expressing MSN (D2-MSN) stimulation. However, the molecular mechanisms controlling balance of activity between D1-MSNs and D2-MSNs during relapse-like drug seeking remain unknown. We show here that the activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), plays an essential role in this process. First, using a novel NPAS4-TRAP (Targeted Recombination in Active Populations) mouse combined with chemogenetics, we found that neurons expressing NPAS4 during cocaine conditioning are required for future drug seeking. In addition, using cell type-specific manipulations, we discovered that NPAS4 is required in D2-MSNs, but not D1-MSNs, for drug seeking in multiple behavioral models of SUD. Single-cell transcriptomic analyses of NAc tissues from drug-experienced mice revealed that that NPAS4 regulates numerous genes in D2-MSNs linked to synapse plasticity, SUD, and drug-related behavior. NPAS4 in NAc D2-MSNs also blocks cocaine experience-dependent strengthening of glutamatergic prefrontal cortical (PFC) inputs onto those neurons, which allows drug cues to activate D1-MSNs and trigger drug-seeking behavior. As such, our findings reveal a novel, cell type-specific function for NPAS4 to enable relapse-like behavior by selectively preventing drug experience-dependent potentiation of the PFC->NAc:D2-MSN circuit. Finally, there is high comorbidity between SUD and stress-induce neuropsychiatric disorders. Chronic stress can produce reward system deficits (e.g. anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC), though the molecular mechanisms remain unclear. We show that NPAS4 in the mPFC is regulated by chronic social defeat stress (CSDS) and that it’s required in this brain region for CSDS-induced changes in natural reward motivation. Additionally, mPFC NPAS4 is required for CSDS-induced reductions in pyramidal neuron dendritic spine density, and transcriptomic analysis from the mPFC revealed that NPAS4 influences expression of genes that are also dysregulated in common neuropsychiatric disorders. Together our findings reveal an essential role for the activity-regulated transcription factor, NPAS4, in both cocaine-conditioned behaviors and chronic stress-induced anhedonia, providing a novel mechanistic insight into potential pharmacotherapeutic treatments for comorbidity between SUDs and stress-related neuropsychiatric disorders.

Rights

All rights reserved. Copyright is held by the author.

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