Hippocampal modulation of subcortical circuits in the control of emotional behavior

项目摘要 几乎三分之一的美国成年人患有焦虑症， 个人、社会和经济负担。焦虑症是一种复杂的基于回路的疾病， 由于许多分布区域、连接和细胞类型的功能障碍， 产生正常的适应行为。因此，更深入地了解这些神经回路 如果我们希望产生新的， 治疗。近年来，我们已经证明腹侧海马（vHPC）是一个中枢神经系统， 扩展电路中生成自适应回避行为的节点。然而，输入- 腹侧海马在焦虑相关行为控制中的输出组织 仍然知之甚少。在这里，我们将使用大量的功能成像， 解剖学定义的vHPC神经元，这些神经元的光学操作，以及高分辨率 行为分析，以扩大我们对扩展腹侧海马 网络控制行为。我们将首先确定vHPC输出的编码属性 神经元到皮质下区域，已知这些区域驱动回避和焦虑样行为。那就 采用新的无监督行为分类工具，以了解与焦虑相关的 行为，以确定vHPC投射神经元如何协调不同的行为 states.最后，我们将确定如何不同的输入差异调制回避 vHPC中与焦虑相关的行为和形状表征。这将提供最详细的 控制回避行为的扩展海马回路的功能图，以及 为产生治疗焦虑症的治疗剂提供了新的靶点。

Project Summary Almost a third of adult Americans suffer from an anxiety disorder, carrying an enormous personal, societal and financial burden. Anxiety disorders are complex circuit-based conditions, resulting from dysfunction in a number of distributed regions, connections, and cell types that generate normal adaptive behavior. Thus, a deeper understanding of how these neural circuits become disrupted to generate maladaptive behavior is crucial if we hope to generate new treatments. In recent years, we have shown that the ventral hippocampus (vHPC) is an central node in the extended circuit that generates adaptive avoidance behavior. However, the input- output organization of the ventral hippocampus in the control of anxiety-related behavior remains poorly understood. Here, we will use functional imaging of large populations of anatomically defined vHPC neurons, optical manipulation of these neurons, and high resolution behavioral analyses to expand our understanding of how the extended ventral hippocampal network controls behavior. We will first determine the encoding properties of vHPC output neurons to subcortical areas known to drive avoidance and anxiety-like behavior. Then, we will adopt new unsupervised behavioral classification tools for understanding anxiety-related behavior in mice to determine how vHPC projection neurons orchestrate distinct behavioral states. Finally, we will determine how distinct inputs to the differentially modulate avoidance behavior and shape anxiety-related representations in vHPC. This will provide the most detailed functional map of the extended hippocampal circuit that controls avoidance behavior, and provide novel targets for generation of therapeutics for the treatment of anxiety disorders.