Relapse to drug-seeking behavior is regulated by medial habenula NR4A2 in male and female mice

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Project Summary/Abstract Substance use disorder is complicated by a lifelong risk of relapse. Relapse vulnerability is programed partly during drug use, when the action of drugs of abuse in the reward circuit enables the formation of abnormally strong context/reward memories. These memory processes underlie common relapse triggers such as exposure to drug-associated cues or environments and can be extremely long lasting. This persistence may be attributed to epigenetics (i.e. modulation of gene expression that occurs through altered chromatin structure without fundamental changes to the DNA sequence itself), which has been shown to establish stable changes in cell function, and in turn changes in behavioral outcomes. This proposal is focused on examining the molecular and cellular mechanisms that may be involved in reinstatement. Recent studies have begun to implicate the MHb in cocaine-associated behaviors, yet the role of the MHb in regulating reinstatement of cocaine self-administration remains largely unknown. Recent work in the lab has identified the histone deacetylase 3 (HDAC3; a powerful epigenetic regulator of gene expression) target gene, Nr4a2, as an important regulator of cocaine-associated behavior. NR4A2 is a transcription factor that regulates aspects of dopamine signaling during development, and is densely expressed in the MHb. I will test the central hypothesis that the MHb regulates reinstatement of cocaine self-administration in an NR4A2-dependent manner. Specifically, I will examine the role of Nr4a2, in MHb-dependent reinstatement of cocaine self-administration using viral expression of NURR2C, an endogenously occurring NR4A2 dominant negative splice variant, or wild-type NR4A2 to bidirectionally regulate NR4A2 function. My preliminary data show that NURR2C animals have reduced reinstatement, identifying NR4A2 in the MHb as a key regulator of reinstatement behavior. To develop a more in-depth understanding of the MHb response to cocaine-seeking behavior as well as self-administration, extinction training, and withdrawal, I will use single nuclei RNA sequencing to look for changes in cell type proportions, gene expression and gene networks. Within these analyses I will also look for NR4A2-dependent changes and sex-dependent changes. Completion of the proposed research will significantly advance our understanding of the MHb in reinstatement, and provide important insight into NR4A2 and NR4A2-dependent gene regulation. This training fellowship will allow me to develop molecular and bioinformatics expertise. With the guidance of both Dr. Wood and Dr. Swarup and the research and professional development environment at UCI, this fellowship will provide a foundation for a successful career as an independent investigator focused on understanding the molecular mechanisms of learning and memory that contribute to relapse to drug-seeking behavior.