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

项目总结 这项创新新科学家(大脑)生物行为研究奖提案的目标是 方案是了解典型和非典型青少年对奖赏处理和冲动的发展 行为。这些复杂的表型在包括注意力缺陷在内的许多精神疾病中都存在。 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 失控奖赏加工和无序冲动的出现，以及 潜在的神经回路被认为是负责的。然而，目前还不清楚是什么因素推动了发展 目前尚不清楚病理是如何通过神经回路的变化来编码的。 青少年大脑认知发展(ABCD)对人脑和行为的纵向研究 目前正在确定青春期预测冲动和其他与奖励相关的表型的因素。 来自小鼠的类似的纵向数据是必要的，以允许分子、细胞和电路级别的询问 青少年发展。这些知识对于有针对性的干预措施是至关重要的，以改变和预防 发育病理学。这一建议为小鼠ABCD研究开发了一个框架。我们使用一种创新的 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适应。这项建议侧重于 5-羟色胺调节皮质纹状体投射对青少年奖赏加工成熟的影响 冲动。使用转基因小鼠品系进行细胞类型和特定时间段的操作，我们将 研究5-羟色胺调节青春期发育轨迹的电路水平机制。这个 在青少年中使用体内钙成像的高风险、高回报将揭示单个细胞和整体- 青春期大脑中发生的支持青春期行为成熟的水平变化。vbl.使用 显微内窥镜技术我们将在整个青春期识别细胞水平的神经变化，并且 定义病理性发展的轨迹。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赏加工和冲动有关的发育病理。 我们的结果将为旨在调节5-羟色胺信号通路的药物疗法的改进提供信息。 青少年用于治疗抑郁症、焦虑症和强迫症。这项研究项目 非常适合为大脑提供资金，因为它直接解决了NIMH的两个关键目标 战略规划，运用新的方法和技术，促进我们对专业的理解 关于是什么驱使青少年成熟的概念性问题。作为一名早期的职业调查员，为此提供资金 雄心勃勃的计划，我唯一有能力执行的，将允许我推出一个创新的基础设施 旨在了解奖励处理和冲动的非典型发展的研究项目。

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.