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: 10310429
• 负责人: Benjamin Hobson
• 金额: $ 5.18万
• 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 2023-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310429
• 关键词: Academic Medical Centers; Address; Adolescence; Adolescent; Adolescent Development; Adult; Affect; Afferent Neurons; Affinity Chromatography; Algorithms; Amphetamines; Award; Axon; Behavioral; Biochemical; Biology; Brain; Candidate Disease Gene; Cell Death; Cells; Cellular biology; Clinical; Clinical Skills; Cognitive deficits; 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; Genetic Translation; Goals; Growth Cones; Health; Knowledge; Link; Logic; Mediating; Mentorship; Messenger RNA; Methodology; Midbrain structure; Mus; NTN1 gene; Neurons; Neurosciences; Nucleus Accumbens; Pattern; Pharmacology; Phosphorus 32; Physicians; Physiology; Positioning Attribute; Prefrontal Cortex; Process; Prosencephalon; Protein Biosynthesis; Proteins; Regulation; Regulator Genes; Research; RiboTag; Ribosomes; Risk; Role; Sampling; Scientist; Shapes; Signal Transduction; Slice; Social outcome; Structure; Substance Use Disorder; Systems Biology; Technical Expertise; Testing; Training; Transgenic Mice; Translating; Translational Regulation; Translations; addiction; adolescent drug use; adverse outcome; axon growth; axon guidance; career; cell type; 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 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; postnatal; postnatal development; pre-doctoral; presynaptic; prevent; programs; psychostimulant; ranpirnase; 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.

毒品使用的早期倡议与长期社会结果不良和较高的底物相关 在成年时使用疾病。在前脑电路中改变多巴胺（DA）神经传递是毒品的标志 这些电路的成瘾和DA输入继续成熟到青少年。最近的证据表明 青少年药物暴露改变了轴突成熟并破坏适当的前脑发育，导致 持续的行为改变可能会增加吸毒的风险。为了防止长期 与青少年吸毒有关的不良结果，我们必须了解药物的机制 滥用会改变DA神经元的正常发育。 DA神经元的产后发育很复杂：一个小 DA神经元的数量必须在两轮细胞死亡中生存，并在广泛的 前脑结构，表明对发展基因表达程序的严格调节。这些DA 神经元发展计划可能特别容易受到苯丙胺的影响，苯丙胺是一种心理刺激药物 在青少年早期进行治疗时，会导致前脑DA神经的持久变化。 该提案将在产后跨DA神经元中的基因表达进行精确的理解 开发并将分析青少年早期的苯丙胺暴露如何改变正常基因表达 模式。神经解剖学，生化，下一代测序与系统生物学的结合 方法将应用于一种转基因小鼠，该小鼠可以实现DA神经元特异性，全基因组的分析 翻译mRNA。 AIM 1将确定与1）关键过渡相关的基因表达变化 与轴突生长和细胞死亡有关的时间点，早期发育和2）对 青少年的苯丙胺暴露并在产后后期发育期间长时间的轴突成熟。细胞 特定于类型的表达数据将用于阐明和验证控制DA的主调节基因 神经元成熟。 AIM 2将探讨亚细胞mRNA定位和蛋白质合成在 在AIM 1（即跨产后发展和 苯丙胺暴露）。拟议的研究将增强我们对DA神经元细胞的理解 生物学将对药物成瘾的神经发育起源具有很大的影响。这个预先 博士奖学金将支持哥伦比亚大学医学的申请人进行严格的科学培训 中心。具有独特专业知识的跨学科心态团队将提供两种神经科学的培训 和系统生物学，增强了申请人的技术技能和专业发展。 还将接受广泛的临床培训，完善一般临床技能并提供特定场地的暴露 与申请人对神经精神病学的兴趣有关。根据该奖项提出的活动将提供 申请人具有发展作为独立身体科学家成功职业所需的技能。