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.

项目概要 创新新科学家生物行为研究奖（BRAINS）提案的目标 计划的目的是了解典型和非典型青少年奖励处理和冲动的发展 行为。这些复杂的表型存在于许多精神疾病中，包括注意力缺陷 多动症、边缘性人格障碍和精神分裂症。青春期是一个敏感期 奖励处理失调和冲动紊乱的出现，以及 潜在的神经回路被认为是负责的。但尚不清楚推动发展的因素有哪些 朝着病理轨迹发展，目前尚不清楚神经回路的变化如何编码病理学。 青少年大脑认知发展（ABCD）对人类大脑和行为的纵向研究是 正在进行中以确定青春期预测冲动和其他与奖励相关的表型的因素。 来自小鼠的类似纵向数据对于允许分子、细胞和电路水平的询问是必要的。 青少年的发展。这些知识对于有针对性的干预措施至关重要，以改变和预防 发育病理学。该提案为小鼠 ABCD 研究开发了一个框架。我们使用创新的 测量家庭笼中复杂行为表型的方法，允许在时间尺度上进行测试 与评估青春期的动态变化兼容。该提案的重点是 皮质纹状体投射的血清素调节促进青少年奖励处理的成熟 冲动。使用转基因小鼠系进行细胞类型和特定时间段的操作，我们将 研究青少年发育轨迹的血清素调节的回路水平机制。这 在青少年中高风险、高回报地使用体内钙成像将揭示单细胞和细胞群 青少年大脑中发生的水平变化支持青少年行为成熟。使用 显微内窥镜技术，我们将识别整个青春期细胞水平的神经变化，以及 定义病理发展的轨迹。这些研究将指出一个时间表和机制 有针对性地预防和治疗与奖励处理和冲动相关的发育病理学。 我们的结果将为旨在调节血清素信号传导的药物疗法的改进提供信息 用于治疗青少年抑郁症、焦虑症和强迫症。本研究项目 非常适合 BRAINS 资助，因为它直接解决 NIMH 的两个关键目标 战略计划并应用新颖的方法和技术来增进我们对专业的理解 是什么推动青少年成熟的概念问题。作为一名早期职业调查员，为此提供资金 雄心勃勃的提案，我有独特的能力来执行，这将使我能够启动一个创新的基础 研究计划旨在了解奖励处理和冲动的非典型发展。