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，携带着巨大的 个人、社会和经济负担。焦虑症是一种复杂的以电路为基础的疾病， 由许多分布区域、连接和细胞类型的功能障碍引起的 生成正常的自适应行为。因此，对这些神经回路是如何 被扰乱以产生不适应行为是至关重要的，如果我们希望产生新的 治疗。近年来，我们发现腹侧海马区(VHPC)是中枢 扩展电路中生成自适应回避行为的节点。然而，投入- 腹侧海马区输出组织在焦虑相关行为控制中的作用 人们对此仍然知之甚少。在这里，我们将使用大量人群的功能成像 解剖定义的vHPC神经元、这些神经元的光学操作以及高分辨率 行为分析，以扩大我们对扩大的腹侧海马体 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，已知可以驱动回避和焦虑样行为。那么，我们会 采用新的非监督行为分类工具来理解与焦虑相关的 小鼠行为以确定vHPC投射神经元如何协调不同的行为 各州。最后，我们将确定差异调制回避的不同输入 VHPC中与行为和形状焦虑相关的表征。这将提供最详细的 控制回避行为的扩展海马区回路的功能图，以及 为治疗焦虑症的疗法的产生提供新的靶点。

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.