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

成熟多巴胺神经元中的基因表达程序：时间调节、亚细胞定位和安非他明的改变

• 批准号: 10532211
• 负责人: Benjamin Hobson
• 金额: $ 3.57万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532211
• 关键词: Academic Medical Centers; Adolescence; Adolescent; Adolescent Development; Adult; Affect; Afferent Neurons; Affinity Chromatography; Algorithms; Amphetamines; Award; Axon; Behavioral; Binding; Biochemical; Biology; Brain; Candidate Disease Gene; Cell Death; Cells; Cellular biology; Clinical Skills; Cognitive deficits; Collaborations; Complex; Corpus striatum structure; DCC gene; Data; Development; Developmental Gene; Developmental Gene Expression Regulation; Developmental Process; Disease; Dopamine; Dorsal; Drug Addiction; Drug Exposure; Drug usage; Drug user; Embryo; Exposure to; Fellowship; Forebrain Development; Functional disorder; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Growth Cones; Health; Knowledge; Link; Logic; Mediating; Mentorship; Messenger RNA; Methodology; Midbrain structure; Mus; NTN1 gene; Neuroanatomy; Neuronal Differentiation; Neurosciences; Nucleus Accumbens; Pattern; Phosphorus 32; Physicians; Physiology; Positioning Attribute; Predisposition; Prefrontal Cortex; Process; Prosencephalon; Protein Biosynthesis; Protein Synthesis Induction; Proteins; Regulation; Regulator Genes; Research; RiboTag; Ribosomes; Risk; Role; Sampling; Scientist; Shapes; Signal Transduction; Slice; Social outcome; Structure; Substance Use Disorder; Synaptic plasticity; Systems Biology; Technical Expertise; Testing; Training; Transgenic Mice; Translating; Translational Regulation; Translations; addiction; adolescent drug use; adverse outcome; axon growth; axon guidance; carcinogenesis; career; cell type; clinical training; differential expression; dopaminergic neuron; drug of abuse; early adolescence; early onset drug use; experience; extracellular; genome-wide; genome-wide analysis; in vivo; interest; knock-down; mRNA Translation; mRNA sequencing; nerve supply; netrin receptor; neuron development; neuron loss; neuronal cell body; neuropsychiatric disorder; neuropsychiatry; neurotransmission; new technology; next generation sequencing; novel; novel sequencing technology; pharmacologic; postnatal; postnatal development; pre-doctoral; presynaptic; prevent; programs; psychostimulant; response; retinal neuron; ribosome profiling; skills; small hairpin RNA; synaptogenesis; translatome

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.

早期开始吸毒与长期不良的社会后果和较高的吸毒率有关