Impact of BDNF on the Development of Social Behavior Circuits

项目摘要 社会行为障碍是许多精神疾病中常见的高度致残性症状， 包括出现在青春期和青年期的抑郁症和焦虑症。本征 社会行为结果的复杂性使得理解其潜在的神经相关性变得困难。 特别是，调节社会行为回路的发展和功能的分子机制 仍然在很大程度上未知。在这种情况下，一个潜在的候选分子是脑源性神经营养因子 脑源性神经营养因子（BDNF）是神经元突触可塑性的关键调节因子，与抑郁和焦虑有关 这种基因在大脑中也有高度表达，与社会行为有关。我们的核心假设是 BDNF是青春期前后关键的眶额皮层正常发育所必需的， （OFC）-杏仁核回路，支持社会接近行为。在啮齿类动物中进行的多项研究，非人类 灵长类动物和人类表明，眶额皮层支持成本效益决策，并编码和更新 代表未来结果的预期值，这表明OFC可能在激励 社会接近行为我们在BDNF功能丧失小鼠系中的大量初步数据支持 在青少年期OFC-杏仁核回路的发育中需要BDNF的前提， 社会功能我们建议评估BDNF对这种结构和功能发育的影响， 青少年时期的OFC-杏仁核回路。我们将使用活钙成像技术（纤维 光度测定法）来记录该回路在一系列社会行为期间的活动。此外，我们将使用 双向调节这些神经元的活性，并更精确地描绘 哪些社会行为是由眶额皮层投射调节的。最后，我们将利用新开发的 用于BDNF信号传导的电路特异性和发育定时操纵的病毒试剂。我们的研究是 旨在确定BDNF在青春期的新作用，以建立皮质杏仁核的最佳功能 与社会行为有关的电路。

Project Summary Social behavioral impairments are common and highly disabling symptoms in many psychiatric disorders, including depression and anxiety disorders that emerge in adolescence and young adulthood. The intrinsic complexity of social behavioral outcomes have made understanding their underlying neural correlates difficult. In particular, the molecular mechanisms regulating the development and function of social behavioral circuits remain largely unknown. In this context, one potential candidate molecule is brain-derived neurotrophic factor (BDNF), a key regulator of neuronal synaptic plasticity that has been implicated in depression and anxiety disorders, and is also highly expressed in brain regions implicated in social behaviors. Our central hypothesis is that BDNF is required for the proper development during a peri-adolescent timeframe of a key orbitofrontal cortex (OFC)-to-amygdala circuit that supports social approach behavior. Multiple studies in rodents, non-human primates, and humans indicate that the OFC supports cost-benefit decision making, and encodes and updates representations of the expected value of future outcomes, suggesting that the OFC may play a role in motivating social approach behavior. Our extensive preliminary data in loss-of-function BDNF mouse lines support the premise of the requirement of BDNF in the peri-adolescent development of OFC-amygdala circuits related to social function. We propose to assess the impact of BDNF on the structural and functional development of this OFC-to-amygdala circuit during the peri-adolescent period. We will use a live calcium imaging technique (fiber photometry) to record the activity of this circuit during a repertoire of social behaviors. In addition, we will use chemogenetic tools to bi-directionally modulate the activity of these neurons and to delineate more precisely what aspects of social behavior are mediated by these OFC projections. Finally, we will utilize newly developed viral reagents for circuit-specific and developmentally-timed manipulations of BDNF signaling. Our studies are designed identify a new role for BDNF during peri-adolescence to establish optimal function of cortico-amygdala circuits related to social behaviors.