Network dynamics of vHip-amygdala-mPFC circuit in innate and learned anxiety

描述（由申请人提供）：焦虑症包括一系列具有不同病因的行为。例如，广泛性焦虑障碍（GAD）是一种先天和慢性恐惧的状态，而创伤后应激障碍（PTSD）是一种对习得性恐惧的焦虑反应，是获得性和线索依赖的。这项提议的主要目标是确定大脑相关区域处理这两种焦虑的不同方式。研究已经确定杏仁核基底外侧复合体（BLA）、内侧前额叶皮层（mPFC）和海马体腹侧部分（vHip）对焦虑处理的各个方面都很重要。提出的工作将解离行为驱动的动态网络形成的这三个区域在学习和先天焦虑。vHip、BLA和mPFC是直接相连的，表明它们形成了一个网络，其相互作用可能构成习得性和慢性焦虑表型的基础。事实上，vHip和BLA向mPFC有收敛的输入，这被认为是在皮层中整合焦虑和环境信息的一种手段。单独的研究表明，在先天焦虑范式中，vHip和mPFC增加了它们的沟通，而条件恐惧增加了海马体和BLA之间的同步。相反，在消除习得性恐惧的过程中，前额叶皮层和杏仁核被认为是一致的。然而，关于mPFC、BLA和vHip如何整合或区分先天焦虑和习得焦虑的数据缺乏。因此，我们的目标是研究这个回路的网络动力学，使用体内的慢性多位点记录，并结合行为分析来探测这两种类型的焦虑。我们将检验这一假设，即vHip、BLA和mPFC之间存在可分离的合作水平，这是所经历的焦虑引发情景的函数。此外，行为和电生理记录将被用来验证5HT1A受体信号的破坏（一个已建立的海马依赖性焦虑模型）将通过增加vHip-mPFC耦合来增强先天焦虑，同时保留完整的杏仁核-海马信号以及习得性焦虑。鉴于焦虑症在美国和世界范围内的流行，以及它们的高死亡率和高社会成本，这一提议的转化性质无疑对公共卫生有益。特别是，通过研究腹侧海马体、杏仁核和内侧前额叶皮层在不同焦虑情境下相互作用的变化方式，我们旨在为区分人类习得性焦虑和先天焦虑提供一种网络层面的方法。这项工作的最终目标是创建一个针对病因的焦虑治疗框架。

DESCRIPTION (provided by applicant): Anxiety disorders include a broad repertoire of behaviors with differing etiologies. For instance, generalized anxiety disorder (GAD) is a state of innate and chronic fear, whereas post-traumatic stress disorder (PTSD) is an anxious response to learned fear that is acquired and cue dependent. The main goal of this proposal is to identify the differing ways in which implicated brain regions process these two types of anxiety. Research has identified the basolateral complex of the amygdala (BLA), the medial prefrontal cortex (mPFC) and the ventral portion of the hippocampus (vHip) as important for various aspects of anxiety processing. The proposed work will dissociate the behavior-driven dynamics of the network formed by these three areas during learned versus innate anxiety. The vHip, BLA and mPFC are directly connected, suggesting that they form a network, the interactions of which could constitute the basis for learned and chronic anxiety phenotypes. Indeed, the vHip and BLA have convergent inputs to the mPFC, which has been suggested as a means of integrating anxiety and context information in the cortex. Separate studies have demonstrated that in innate anxiety paradigms, the vHip and mPFC increase their communication, whereas conditioned fear increases synchrony between the hippocampus and BLA. In contrast, the mPFC and amygdala are thought to act in concert during extinction of learned fear. However, data is lacking on how the mPFC, BLA and vHip integrate or differentiate innate versus learned anxiety. Therefore, we aim to study the network dynamics of this circuit using chronic multisite recordings in vivo in conjunction with behavioral assays probing both types of anxiety. We will test the hypothesis that there are dissociable levels of cooperation between the vHip, BLA and mPFC as a function of the anxiety provoking scenario that is experienced. In addition, behavior and electrophysiological recordings will be used to test the idea that disruption of 5HT1A receptor signaling, an established model of hippocampal dependent anxiety, will enhance innate anxiety via increased vHip-mPFC coupling, while leaving intact amygdala-hippocampal signaling as well as learned anxiety. Given the prevalence of anxiety disorders in the United States and worldwide, as well as their high mortality and high cost to society, the translational nature of this proposal is undoubtedly beneficial to public heath. In particular, by examining the changing ways in which the ventral hippocampus, amygdala and medial prefrontal cortex interact during different anxiogenic scenarios, we aim to provide a network-level approach for differentiating between learned and innate anxiety in humans. The ultimate goal of this work is to create a framework for etiology-tailored therapies of anxiety.