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

描述(由申请者提供)：焦虑症包括一系列不同病因的行为。例如，广泛性焦虑症(GAD)是一种与生俱来的慢性恐惧状态，而创伤后应激障碍(PTSD)是对后天获得性恐惧的焦虑反应，依赖于线索。这项建议的主要目的是确定大脑相关区域处理这两种类型焦虑的不同方式。研究发现，杏仁核基底外侧复合体(BLA)、内侧前额叶皮质(MPFC)和海马体腹侧部分(VHip)对焦虑处理的各个方面都很重要。这项拟议的工作将分离这三个区域在后天焦虑和先天焦虑期间形成的网络的行为驱动动态。VHIP、BLA和mPFC是直接相关的，这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对mPFC的输入是一致的，mPFC被认为是一种整合焦虑和大脑皮层背景信息的手段。单独的研究表明，在先天焦虑的范例中，VHIP和mPFC增加了它们之间的交流，而条件性恐惧增加了海马体和BLA之间的同步性。相比之下，mPFC和杏仁核被认为是在后天恐惧消退的过程中协同行动的。然而，缺乏关于mPFC、BLA和VHIP如何整合或区分先天焦虑和后天焦虑的数据。因此，我们的目标是使用活体中的慢性多点记录结合探测这两种类型的焦虑的行为分析来研究这一回路的网络动力学。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，作为所经历的引发焦虑的情景的函数。此外，行为和电生理记录将被用来测试这一想法，即破坏5HT1a受体信号将通过增加VHip-mPFC偶联来增强先天焦虑，同时保留完整的杏仁核-海马区信号和后天焦虑。5HT1a受体信号是已建立的海马区依赖焦虑的模型。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，这项提议的翻译性质无疑对公众健康有利。特别是，通过研究腹侧海马体、杏仁核和内侧前额叶皮质在不同导致焦虑的场景中相互作用的方式的变化，我们的目标是提供一种网络水平的方法来区分人类的后天焦虑和先天焦虑。这项工作的最终目标是为焦虑症的病因定制治疗创建一个框架。

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.