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

• 批准号: 7806851
• 负责人: Ekaterina Likhtik
• 金额: $ 4.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-12 至 2012-01-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806851
• 关键词: Accounting; Affect; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Area; Beds; Behavior; Behavioral; Behavioral Assay; Brain region; Cell Nucleus; Chronic; Communication; Complex; Coupling; Cues; Data; Disease remission; Dorsal; Economic Burden; Elements; Etiology; Extinction (Psychology); Fright; Generalized Anxiety Disorder; Goals; Health; Hippocampus (Brain); Human; Knock-out; Knockout Mice; Learning; Left; Medial; Mental disorders; Modeling; Mus; Nature; Pattern; Phenotype; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevalence; Price; Process; Receptor Signaling; Research; Rice; Signal Transduction; Societies; Sum; Testing; Time; United States; Walkers; Work; base; conditioned fear; cost; driving behavior; effective therapy; experience; in vivo; learning extinction; mortality; mouse model; novel; receptor; relating to nervous system; response

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）是一种对习得性恐惧的焦虑反应，这种恐惧是后天获得的，依赖于线索。这项研究的主要目的是确定大脑区域处理这两种类型焦虑的不同方式。研究已经确定杏仁核的基底外侧复合体（BLA），内侧前额叶皮层（mPFC）和海马体的腹侧部分（vHip）对焦虑处理的各个方面都很重要。拟议的工作将解离的行为驱动的动态网络形成的这三个领域在学习与先天焦虑。vHip，BLA和mPFC直接连接，这表明它们形成了一个网络，其相互作用可以构成学习和慢性焦虑表型的基础。事实上，vHip和BLA对mPFC有会聚的输入，这被认为是在皮层整合焦虑和背景信息的一种手段。独立的研究表明，在先天焦虑范式中，vHip和mPFC增加了它们的交流，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消除习得性恐惧的过程中协调行动的。然而，缺乏关于mPFC，BLA和vHip如何整合或区分先天与习得性焦虑的数据。因此，我们的目标是研究这个电路的网络动力学使用慢性多位点记录在体内结合行为检测探测两种类型的焦虑。我们将测试这样的假设：vHip、BLA和mPFC之间存在可分离的合作水平，这是所经历的焦虑激发场景的函数。此外，行为和电生理记录将被用来测试的想法，5HT1A受体信号传导，海马依赖性焦虑的一个既定模型的中断，将通过增加vHip-mPFC耦合增强先天性焦虑，而留下完整的杏仁核-海马信号以及学习焦虑。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，这一建议的转化性质无疑有利于公共卫生。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中相互作用的变化方式，我们的目标是提供一个网络水平的方法来区分人类的学习和先天焦虑。这项工作的最终目标是创建一个框架，为病因量身定制的焦虑疗法。