Gene Expression Programs in Maturing Dopamine Neurons: Temporal Regulation, Subcellular Localization, and Alteration by Amphetamine

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Early initiation of drug use is associated with long-term poor social outcomes and higher rates of substance use disorders in adulthood. Altered dopamine (DA) neurotransmission in forebrain circuits is a hallmark of drug addiction and DA inputs to these circuits continue to mature into adolescence. Recent evidence suggests that adolescent drug exposure alters DA axonal maturation and disrupts proper forebrain development, resulting in persistent behavioral alterations that may increase the risk of drug addiction. In order to prevent long-term adverse outcomes related to adolescent drug use, we must understand the mechanisms by which drugs of abuse alter normal development of DA neurons. Postnatal development of DA neurons is complex: a small number of DA neurons must survive two rounds of cell death and mature their axonal innervation in expansive forebrain structures, suggesting tight regulation of developmental gene expression programs. These DA neuron developmental programs may be particularly susceptible to amphetamine, a psychostimulant drug of abuse that causes lasting changes in forebrain DA innervation when administered during early adolescence. This proposal will develop a precise understanding of gene expression in DA neurons across postnatal development and will analyze how early adolescent amphetamine exposure alters normal gene expression patterns. A combination of neuroanatomical, biochemical, next-generation sequencing, and systems biology approaches will be applied to a transgenic mouse that enables DA neuron-specific, genome-wide analysis of translating mRNAs. Aim 1 will identify changes in gene expression associated with 1) key transitional timepoints related to axonal growth and cell death in early postnatal development and 2) response to adolescent amphetamine exposure and prolonged axonal maturation during later postnatal development. Cell type-specific expression data will be used to elucidate and validate master regulator genes controlling DA neuron maturation. Aim 2 will explore the role of subcellular mRNA localization and protein synthesis in maturing DA neurons across the same conditions studied in Aim 1 (i.e., across postnatal development and following amphetamine exposure). The proposed research will enhance our understanding of DA neuronal cell biology and will have far reaching implications for the neurodevelopmental origins of drug addiction. This pre- doctoral fellowship will support rigorous scientific training of the applicant at Columbia University Medical Center. An interdisciplinary mentorship team with unique expertise will provide training in both neuroscience and systems biology, enhancing the applicant’s technical skills and professional development. The applicant will also undergo extensive clinical training, refining general clinical skills and providing field-specific exposure relevant to the applicant’s interest in neuropsychiatry. The activities proposed under this award will provide the applicant with the skills required to develop a successful career as an independent physician-scientist.