The influence of peroxisome proliferator-activated receptor gamma coactivator - 1 alpha (PGC-1a) on the nucleus accumbens during cocaine-self-administration

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Project Summary/Abstract Addiction to drugs of abuse exacts massive economic and human costs upon society. Drug addiction is often characterized by persistant drug seeking and vulnerability to relapse, which are huge barriers to addiction treatment. Relapse can occur even after prolonged abstinence and is often preceded by robust drug craving precipitated by exposure to drug-paired stimuli and environments. This psychological persistence in drug craving and seeking is tied to neurobiological changes of natural reward related systems by drugs of abuse. However, the cell type-specific molecular mechanisms by which neuroplasticity takes place following drug consumption is incompletely understood. A growing body of work indicates mitochondrial health and regulation are important for neuronal modifications associated with substance use disorders and psychiatric illness. Here, I aim to identify how cocaine alters transcriptional regulation within D1- medium spiny neurons (D1-MSNs) via the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC- 1α). Previous work and preliminary data show that cocaine increases PGC-1α expression specifically in D1- MSNs, increases D1-MSN spine density, and increases the number of small mitochondria via increased mitochondrial fission. Further, exogenously increasing PGC-1α exaggerates cocaine-related behaviors like locomotor sensitization and conditioned place preference. Despite these findings, a causal link between PGC- 1α and the spine and mitochondrial changes observed in D1-MSNs after cocaine has not been demonstrated, nor has the necessity of PGC-1α for the expression of cocaine seeking behavior been established. I hypothesize that cocaine alters drug seeking behavior, MSN spine density, and mitochondrial morphology by increasing the expression and function of PGC-1α, and that reducing the expression of PGC-1α in D1-MSNs will block this cocaine-induced plasticity. The experiments of Aim 1 of this proposal will test this hypothesis. Further, in Aim 2, I will determine what genes PGC-1α interacts with after cocaine self-administration using chromatin immunoprecipitation. I will then specifically measure the expression of PGC-1α-targeted genes that are involved in mitochondrial and spine plasticity in D1-MSNs after cocaine self-administration. Together, using cutting edge behavioral and molecular techniques, these experiments will establish the importance of PGC-1α in cocaine- induced molecular and cellular changes that mediate cocaine SA and seeking. These aims synthesize my interest in molecular mediators of behavior, my sponsor’s expertise in dissecting cell-type selective gene expression in the striatum, and the experience of the diverse faculty at the University of Maryland School of Medicine to improve our understanding of the neuronal mechanisms mediating drug craving. This work will both improve our potential to predict relapse vulnerability and identify effective pharmacological therapies, and will provide a strong platform to launch my independent career in science