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

先天性和习得性焦虑中 vHip-amygdala-mPFC 回路的网络动力学

基本信息

批准号：
8015593
负责人：
Ekaterina Likhtik
金额：
$ 3.72万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-12 至 2011-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：焦虑症包括具有不同病因的广泛行为。例如，广泛性焦虑症（GAD）是一种先天性和慢性恐惧的状态，而创伤后应激障碍（PTSD）是对习得性恐惧的焦虑反应，这种恐惧是后天获得的且依赖于线索。该提案的主要目标是确定相关大脑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)、内侧前额叶皮层 (mPFC) 和海马体腹侧部分 (vHip) 对于焦虑处理的各个方面都很重要。拟议的工作将在习得性焦虑与先天性焦虑期间分离这三个区域形成的网络的行为驱动动态。 vHip、BLA 和 mPFC 直接相连，表明它们形成一个网络，其相互作用可能构成习得性焦虑表型和慢性焦虑表型的基础。事实上，vHip 和 BLA 对 mPFC 具有聚合输入，这被认为是在皮质中整合焦虑和情境信息的一种手段。单独的研究表明，在先天性焦虑范式中，vHip 和 mPFC 增加了它们的沟通，而条件性恐惧则增加了海马体和 BLA 之间的同步性。相比之下，mPFC 和杏仁核被认为在习得性恐惧消退过程中协同行动。然而，关于 mPFC、BLA 和 vHip 如何整合或区分先天性焦虑和后天性焦虑的数据尚缺乏。因此，我们的目标是使用体内慢性多位点记录并结合探索两种类型焦虑的行为测定来研究该回路的网络动态。我们将检验以下假设：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场景的函数。此外，行为和电生理记录将用于测试这一观点，即破坏 5HT1A 受体信号传导（一种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-海马信号传导以及习得性焦虑。鉴于焦虑症在美国和世界范围内的流行，以及其高死亡率和高社会成本，该提案的转化性质无疑有利于公众健康。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的焦虑情景下相互作用的变化方式，我们的目标是提供一种网络水平的方法来区分人类的习得性焦虑和先天性焦虑。这项工作的最终目标是创建一个针对病因学定制的焦虑疗法的框架。