Drug addiction is a maladaptive form of experience-dependent plasticity that develops following chronic exposure to drugs of abuse. Drug experience induces plasticity of synaptic transmission within the neural circuitry of reward, which is thought to depend upon modulation of gene expression. Preliminary data I acquired demonstrates that chronic exposure to cocaine results in dramatic rewiring of gene regulatory networks within the nucleus accumbens, a key component of the brains’ reward circuitry and a central integrator of synaptic inputs implicated in the formation of addiction.
Understanding the basis for this rewiring of gene regulatory networks, as well as identification and analysis of the neuronal population in which it is expressed, will be a major focus of work in my independent lab. These questions, and their implications for synaptic function and behavior, will be pursued in parallel at multiple levels, addressing the regulation of gene transcription both globally and in a cell-type specific fashion.
The identity of transcriptional programs is defined by the repertoire of transcription regulators expressed in a cell. Preliminary data demonstrates elevated expression of Fos, FosB, CEBPB, KLF2 and ZFP36 in the nucleus accumbens of mice abstinent following chronic cocaine exposure, suggesting that these genes could underlie the rewiring of transcriptional complexes observed in abstinent mice. We will address the function of these genes by virus-mediated shRNA knockdown in the nucleus accumbens, as well as dissociated neuronal cultures. Comprehensive analysis of gene targets of CEBPB and KLF2 will be further pursued by chromatin immunoprecipitation followed by deep sequencing.
This study is expected to result in identification of molecular mechanisms and specific genes responsible for the rewiring of gene regulatory networks observed following repetitive exposure to cocaine, potentially underlying the persistent memory of drug experience driving addiction.
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