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Epigenetic control of medial habenula function in cocaine-associated behaviors

Creative Commons 'BY' version 4.0 license

Drugs of abuse, such as cocaine, are known to cause long-term changes in reward circuitry and, ultimately, persistent changes in behavior. Although many critical nodes in the neural circuitry contributing to relapse of drug-seeking behavior have been identified and studied, a full characterization of the networks driving reinstatement of cocaine-seeking remains lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral (LHb) and medial (MHb) substructures. Recent research has demonstrated a role for the MHb in regulating drug-associated behavior; specifically, the MHb has been shown to be a regulator of nicotine-seeking behavior and nicotine withdrawal. Though there is mounting evidence suggesting the MHb is responsible for various behavioral responses to various drugs of abuse, the position of the MHb in regulating relapse-like behaviors remains tenuous. The present dissertation examined the role of the MHb in regulating reinstatement of cocaine-associated behavior. We demonstrate MHb activity is engaged during relapse of cocaine-associated behavior and driving activity in a subset of the MHb population mimics the reinstatement response. Moreover, we identify a unique epigenetic signature at transcription factor Nr4a2 that is critical for the reinstatement of cocaine-associated behaviors. My studies provide new insight into the role of molecular adaptations within the MHb in regulating substance use disorders.

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