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

项目摘要 该提案的目标是为生物行为研究奖创新的新科学家（大脑） 计划是了解典型和非典型的青少年发展的奖励处理和冲动 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、边缘型人格障碍和精神分裂症。青春期是一个敏感的时期， 奖励处理失调和冲动紊乱的出现，以及 潜在的神经回路然而，目前还不清楚是什么因素推动了发展 病理学的轨迹，并且不知道病理学是如何通过神经回路中的变化编码的。 青少年大脑认知发展（ABCD）对人类大脑和行为的纵向研究是 正在进行的研究，以确定青春期的因素，预测冲动和其他奖励相关的表型。 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。 青少年发展这一知识对于有针对性的干预措施至关重要， 发育病理学该建议为小鼠ABCD研究提供了一个框架。我们使用创新的 一种测量家庭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相一致。本建议侧重于以下方面的作用： 5-羟色胺调节皮质纹状体投射在青少年奖赏加工成熟中的作用， 冲动使用转基因小鼠品系进行细胞类型和时间段特异性操作，我们将 研究青少年发展轨迹的5-羟色胺调节的回路水平机制。的 在青少年中使用体内钙成像的高风险，高回报将揭示单细胞和整体- 发生在青少年大脑中支持青少年行为成熟的水平变化。使用 显微内窥镜技术，我们将确定整个青春期细胞水平的神经变化， 定义一个病理发展的轨迹。这些研究将指出一个时间框架和机制， 有针对性地预防和治疗与奖励处理和冲动有关的发育病理学。 我们的研究结果将为改善药物治疗提供信息，这些药物旨在调节血清素信号， 青少年抑郁症、焦虑症和强迫症的治疗。本研究项目 非常适合BRAINS的资助，因为它直接解决了NIMH的两个关键目标 战略计划，并应用新的方法和技术，以促进我们对主要的理解 是什么推动了青少年的成熟。作为一名早期职业调查员， 一个雄心勃勃的建议，我唯一的装备来实现，将使我能够推出一个创新的基本 一项旨在理解奖励处理和冲动性的非典型发展的研究计划。

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.