Hippocampal modulation of subcortical circuits in the control of emotional behavior

 描述（由申请人提供）：焦虑症，如创伤后应激障碍，广泛性焦虑症和恐慌症折磨着近三分之一的美国人，造成了重大的个人，经济和社会损失。因此，大脑回路的识别 这些疾病中的紊乱会对社会有很大的好处。近年来，人们认识到海马除了在学习和记忆中的作用外，在情绪行为中也起着重要作用。我们最近发现，腹侧海马（vHPC）神经元活动的急性调制可以有力地和可逆地抑制先天性焦虑相关行为。然而，vHPC控制恐惧、焦虑和消极动机行为的机制仍然难以捉摸。在这项提案中，我们将利用光学技术来询问扩展的vHPC电路，以确定它如何控制情绪行为。我们将专注于解构从vHPC到下丘脑和杏仁核的输出，这两个皮质下结构涉及对情绪刺激的自主神经，神经内分泌和动机反应。我们将首先映射控制情绪行为的扩展vHPC网络，确定vHPC调制的细胞类型，以及招募这些输出流的行为刺激。然后，我们将使用特定的项目，光学调制的vHPC终端在杏仁核和下丘脑，以确定vHPC输出流是否在功能上是分离的先天焦虑，厌恶和学习恐惧的贡献。最后，我们将使用细胞类型特异性功能成像来确定vHPC神经元群体的活动中是否存在焦虑状态的神经元签名。这些研究的最终目标是开发一个扩展的vHPC回路的功能图，该回路调节先天和习得性恐惧，为治疗这些使人衰弱的焦虑症提供一个新的靶点。

 DESCRIPTION (provided by applicant): Anxiety disorders such as posttraumatic stress disorder, generalized anxiety disorder, and panic disorder afflict almost one third of Americans with significant personal, financial and societal costs. Thus, identification of the brain circuits that are disordered in these illnesses would have a major benefit to society. In recent years, it has become appreciated that the hippocampus, in addition to its role in learning and memory, plays an important role in emotional behavior. We have recently shown that acute modulation of neuronal activity in the ventral hippocampus (vHPC) can powerfully and reversibly suppress innate anxiety-related behavior. However, the mechanisms by which the vHPC may control fear, anxiety, and negatively motivated behaviors have remained elusive. In this proposal, we will leverage optical techniques to interrogate the extended vHPC circuit to determine how it may control emotional behavior. We will focus on deconstructing the output from the vHPC to the hypothalamus and amygdala, two subcortical structures involved in the autonomic, neuroendocrine and motivational responses to emotionally charged stimuli. We will first map the extended vHPC network that controls emotional behavior, determining the cell-types types modulated by the vHPC, as well as the behavioral stimuli that recruit these output streams. Then, we will use projection-specific, optical modulation of vHPC terminals in the amygdala and hypothalamus to determine whether vHPC output streams are functionally dissociable in their contribution to innate anxiety, aversion and learned fear. Finally, we will use cell-type specific functional imaging to determine whether there exists a neuronal signature for anxiety state within the activity of populations of vHPC neurons. The ultimate goal of these studies is to develop a functional map of the extended vHPC circuit that modulates innate and learned fear, providing a novel target for therapies aimed at the treatment of these debilitating anxiety disorders.