Defining the cell-type specific role of histone acetyltransferase KAT2a in nucleus accumbens D1 medium spiny neurons as a driver of cocaine use disorder

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Cocaine use disorder (CUD) imposes a large burden on public health, particularly because there are no FDA- approved pharmacotherapies for the disorder. The onset and maintenance of CUD is driven by physiological and molecular changes within the brain that lead to maladaptive behavior associated with cocaine taking and seeking. A key neuronal population in this dysregulation is dopamine 1 receptor expressing medium spiny neurons (D1 MSNs) in the nucleus accumbens (NAc). These cells are activated by acute cocaine, undergo physiological and transcriptional plasticity following repeated cocaine exposure, and are recruited by cocaine- associated cues to drive drug seeking. While their causal role in drug-induced behavior has been identified, the molecular mechanisms underlying cocaine-induced dysregulation remains poorly understood. The goal of this proposal is to define how chromatin regulation – through a recently identified cocaine-induced chromatin modifying enzyme [lysine acetyltransferase 2a (KAT2a)] – is a key substrate involved in the motivation to take and seek cocaine. We present in our preliminary data a detailed series of proteomic bioinformatic studies through which we identified KAT2a as an upstream regulator of the wide-scale transcriptional dysregulation associated with cocaine exposure in the NAc of both males and females. We also show that mutations to KAT2a that impair its function only in D1 MSNs greatly impair cocaine self-administration and disrupt physiological responses in D1 MSNs. I hypothesize that KAT2a acts within NAc D1 MSNs to control cocaine self-administration and cue-induced seeking via regulating D1 MSN activity at baseline and in response to drug-associated stimuli. To address this question, I will combine cocaine self-administration in mice with viral-mediated gene transfer and optical imaging in awake and behaving animals. In Aim 1, I will define the role that KAT2a in D1 MSNs plays in motivation to consume cocaine, cocaine reward sensitivity, and cue-induced seeking. In Aim 2, I will use optical imaging to define how KAT2a alters D1 MSN activity at baseline and in response to cocaine. In Aim 3, I will define the role of KAT2a in D1 MSN responses to cocaine-associated cues in awake and behaving animals and determine how these neural dynamics relate to drug-seeking behavior. The training goals in this proposal will provide the technical and conceptual expertise necessary to investigate the transcriptional and epigenetic mechanisms underlying substance use disorder. Finally, the experimental findings will define a cell type-specific neuroepigenetic mechanism of CUD in males and females.