Serotonin modulation of the development of neural circuits underlying reward processing and impulsivity in adolescents

血清素对青少年奖励处理和冲动神经回路发育的调节

• 批准号: 10200242
• 负责人: Katherine M Nautiyal
• 金额: $ 56.9万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10200242
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Aggressive behavior; Anxiety; Attention deficit hyperactivity disorder; Automobile Driving; Award; Basic Science; Behavior; Behavioral; Behavioral Mechanisms; Biological; Borderline Personality Disorder; Brain; Calcium; Cells; Complex; Corpus striatum structure; Data; Development; Disease; Etiology; Event; Funding; Goals; Impulsive Behavior; Impulsivity; Individual; Intervention; Knock-out; Knowledge; Learning; Long-Term Depression; Measures; Mediating; Mental Depression; Mental disorders; Methods; Molecular; Mouse Cell Line; Mus; National Institute of Mental Health; Nature; Neuromodulator; Neurons; Obsessive-Compulsive Disorder; Operant Conditioning; Outcome; Pathologic; Pathology; Pharmacotherapy; Phenotype; Prevention; Process; Research; Research Personnel; Research Project Grants; Rewards; Rodent; Role; Schizophrenia; Scientist; Serotonin; Serotonin Receptor 5-HT1B; Shapes; Signal Transduction; Stimulus; Strategic Planning; Synapses; System; Techniques; Technology; Testing; Time; Transgenic Mice; Work; addiction; base; behavior test; behavioral phenotyping; biobehavior; brain behavior; career; cell type; cognitive development; experimental study; genetic manipulation; high reward; high risk; in vivo calcium imaging; innovation; longitudinal human study; microendoscope; neural circuit; neurodevelopment; neuromechanism; novel; prevent; programs; relating to nervous system; response; reward processing; suicidal

PROJECT SUMMARY The goal of this proposal for the Biobehavioral Research Awards for Innovative New Scientists (BRAINS) program is to understand typical and atypical adolescent development of reward processing and impulsive behavior. These complex phenotypes are found in many psychiatric disorders including attention deficit hyperactivity disorder, borderline personality disorder, and schizophrenia. Adolescence is a sensitive period for the emergence of dysregulated reward processing and disordered impulsivity, and for the development of underlying neural circuits thought to be responsible. However, it is unclear what factors push development towards pathological trajectories and it is unknown how pathology is encoded by changes in neural circuits. The Adolescent Brain Cognitive Development (ABCD) longitudinal study of human brain and behavior is underway to identify factors in adolescence that predict impulsivity and other reward-related phenotypes. Similar longitudinal data from mice are necessary to allow molecular, cellular, and circuit-level interrogation of adolescent development. This knowledge is critical for targeted interventions to alter and prevent developmental pathology. This proposal develops a framework for mouse ABCD studies. We use an innovative approach to measure complex behavioral phenotypes in the homecage that allows for testing on a timescale compatible with assessing the dynamic changes during adolescence. This proposal focuses on the role of serotonin modulation of corticostriatal projections in driving adolescent maturation of reward processing and impulsivity. Using transgenic mouse lines for cell-type and time period-specific manipulations, we will investigate circuit-level mechanisms of serotonin modulation of adolescent developmental trajectories. The high-risk, high-reward use of in vivo calcium imaging in adolescents will uncover the single cell and ensemble- level changes occurring in the adolescent brain that supports adolescent behavioral maturation. Using microendoscope technology we will identify neural changes at the cellular level throughout adolescence, and define a trajectory of pathological development. These studies will point to a timeframe and mechanism for targeted prevention and treatment of developmental pathology related to reward processing and impulsivity. Our results will inform refinement of pharmacotherapies aimed at modulating serotonin signaling in adolescents for the treatment of depression, anxiety, and obsessive compulsive disorder. This research project is highly appropriate for BRAINS funding because it directly addresses two key objectives in the NIMH Strategic Plan and applies novel methods and techniques to advance our understanding of the major conceptual question of what drives adolescent maturation. As an early career investigator, funding for this ambitious proposal, which I’m uniquely equipped to carry out, would allow me to launch an innovative basic research program aimed at understanding the atypical development of reward processing and impulsivity.

项目摘要 这项为创新新科学家（BRAINS）生物行为研究奖提案的目标 计划是要了解奖励处理和冲动的典型和非典型的青少年发展 行为。这些复杂的表型在许多精神疾病中都发现，包括注意力不足 多动症障碍，边缘性人格障碍和精神分裂症。青少年是一个敏感的时期 失调的奖励处理和不当冲动的出现，以及发展 被认为是负责的基本神经回路。但是，目前尚不清楚哪些因素推动开发 走向病理轨迹，尚不清楚病理如何被神经回路的变化编码。 人类脑和行为的青少年脑认知发展（ABCD）是 正在进行鉴定青少年预测冲动性和其他与奖励相关的表型的因素。 必须来自小鼠的类似纵向数据，以允许分子，细胞和电路级的询问 青少年发展。这些知识对于有针对性的干预措施改变和防止 发育病理学。该建议为小鼠ABCD研究开发了一个框架。我们使用创新 测量回家中复杂行为表型的方法，该表型允许在时间尺度上进行测试 与评估青少年期间的动态变化兼容。该提议着重于 皮质纹状体项目的5-羟色胺调节，以推动青少年奖励加工和 冲动。使用转基因小鼠系进行细胞类型和特定时间时期的操作，我们将 研究青少年发育轨迹的5-羟色胺调节的电路级机制。这 在青少年中，高风险的高回报使用体内钙成像将发现单个细胞和集合 - 在青少年大脑中发生的水平变化支持青少年行为成熟。使用 微型内镜技术我们将在整个青少年的细胞水平上确定神经变化， 定义病理发展的轨迹。这些研究将指出一个时间范围和机制 有针对性的预防和治疗与奖励加工和冲动有关的发育病理学。 我们的结果将为旨在调节血清素信号传导的药物治疗的细化提供信息 治疗抑郁症，焦虑和强迫症的青少年。这个研究项目 非常适合大脑资金，因为它直接解决了NIMH中的两个关键对象 战略计划并应用新颖的方法和技术来促进我们对主要的理解 是什么推动了青春期成熟的概念问题。作为早期职业调查员，为此提供资金 雄心勃勃的提议（我非常等同于执行）将使我能够推出创新的基本 研究计划旨在了解奖励处理和冲动的非典型发展。