Substance use disorder is a chronic, relapsing behavioral disorder that is characterized by compulsive drug seeking and use despite negative consequences to the individual. During the course of drug use, there are persistent neuroadaptations that occur in the nucleus accumbens (NAc), a brain region associated with reward and motivation. This region is highly involved in drug reward sensitivity and learning, and dysregulation contributes to multiple phases of addiction. For example, in abstinent addicts, relapse can be triggered by environmental cues associated with previous drug use, but the molecular and cellular mechanisms underlying relapse triggers are not well understood. One possible mechanism is that drug use activates specific populations of neurons that are responsible for the association between reinforced behavior and drug-associated stimuli. Our lab has previously shown that the epigenetic enzyme, histone deacetylase 5 (HDAC5), is critical for cocaine reward-related learning and memory. We are currently testing the hypothesis that a transcription factor and downstream target of HDAC5, neuronal PAS Domain Protein 4 (NPAS4), is involved in the formation of cocaine reward-context memories through its function in a specific subpopulation of neurons in the NAc. NPAS4 is induced rapidly and transiently by glutamatergic synaptic activity, and it regulates excitatory/inhibitory synapse balance and synaptic transmission. NPAS4 also shapes neuronal circuits to encode learned information, and it is induced strongly by exposure to novel drug contexts. The aims laid out in this proposal will determine the cell type-specific role of NPAS4 in cocaine reward-context learning and memory, as well as the role of NPAS4- inducing NAc neurons in the learned association between external cues and cocaine reward experiences. These experiments employ a fusion of transgenic lines with cutting edge viral vector constructs to elucidate the role of NPAS4 in the mechanisms behind drug addiction. All analyses will be performed in mouse models of contingent and non-contingent drug reward learning. The Medical University of South Carolina is a leading center in the substance abuse field and is an ideal location for performing these experiments. In addition, my mentorship under Dr. Christopher Cowan will bolster my training in laboratory techniques, scholarship, career development, and ethics, all of which are necessary for success in my predoctoral training and subsequent academic research career. The comprehensive experimental design of these studies and rigorous application of pioneering techniques will provide fundamental knowledge about the role of NPAS4 in the learning and memory of drug reward and will provide significant learning and development opportunities that will serve as a foundation for my future career in neuroscience.