Exploring the pathophysiology of anxiety: the role of the hippocampus, amygdala a

探索焦虑的病理生理学：海马、杏仁核的作用

基本信息

批准号：
9249654
负责人：
Eduardo David Leonardo
金额：
$ 32.32万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249654
关键词：
Address Adult Amygdaloid structure Anti-Anxiety Agents Anxiety Anxiety Disorders Behavior Brain Brain region Cell Nucleus Data Development Disease Emerging Technologies Environment Exposure to Functional disorder Genetic Genetic Models Goals Hippocampus (Brain)Knock-out Knockout Mice Maps Measures Medial Mental disorders Morbidity - disease rate Mus Nature Neurobiology Neurons Output Pathologic Pathological anxiety Pattern Pharmacogenetics Pharmacology Phenotype Physiological Prefrontal Cortex Property Public Health Role Serotonin Receptor 5-HT1A Societies Structure System Techniques Testing Therapeutic Intervention Work anxiety states anxiety-like behavior anxiety-related behavior anxious avoidance behavior cost emotion regulation experimental study in vivo innovation interest neural patterning neurobiological mechanism neurophysiology novel novel strategies optogenetics public health relevance relating to nervous system targeted treatment tool

项目摘要

DESCRIPTION (provided by applicant): The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key unmet public health goal, as these disorders represent a large burden to society in morbidity and related costs. Our previous studies with wild-type and serotonin 1A- receptor knockout (5-HT1AR KO) mice have implicated a circuit consisting of the ventral hippocampus (vHPC), the basolateral amygdala (BLA), and the medial prefrontal cortex (mPFC) in regulating anxiety-like behavior in various paradigms. Most notably, we have shown that these three regions functionally interact during anxiety, and that the strength of these interactions (1) correlates with anxiety and (2) is greater in the highly anxious 5- HT1AR KO mice than in wild-type littermates. Furthermore, our data suggest that the mPFC uses these interactions to construct a map of the aversiveness of the environment, which in turn is used to guide behavior. However, these observations are primarily correlative in nature. In this renewal application, we propose to directly test the hypothesis that the vHPC and BLA drive neural representations of aversiveness and anxiety-related behavior via their interactions with each other and with the mPFC. We will use a variety of pharmacological, optogenetic and pharmacogenetic tools to silence the vHPC and/or BLA, combined with in vivo neurophysiology to probe the role of these regions in the neural representations of aversiveness within the mPFC as well as anxiety-like behavior. In parallel, we will use emerging technologies aimed at silencing specific projections from and between these brain regions to determine whether and how these specific projections are required. These experiments will be performed in both wild-type and 5-HT1AR KO mice to test their relevance to pathological as well as physiological anxiety mechanisms. Addressing these issues will clarify the mechanisms by which these brain structures modulate anxiety-like behavior, and may help identify specific patterns of connectivity and activity that underly anxiety, providing novel functional targets for therapeutic intervention.

描述（由申请人提供）：当前提案旨在了解焦虑症的神经生物学机制。进一步了解焦虑症仍然是一个未实现的关键公共卫生目标，因为这些疾病在发病率和相关费用方面给社会带来了巨大负担。我们之前对野生型和血清素 1A 受体敲除 (5-HT1AR KO) 小鼠的研究表明，由腹侧海马 (vHPC)、基底外侧杏仁核 (BLA) 和内侧前额叶皮层 (mPFC) 组成的回路在调节中的作用。各种范式中的焦虑样行为。最值得注意的是，我们已经证明这三个区域在焦虑期间功能上相互作用，并且这些相互作用的强度（1）与焦虑相关，并且（2）在高度焦虑的5-HT1AR KO小鼠中比在野生型同窝小鼠中更强。此外，我们的数据表明，mPFC 使用这些相互作用来构建环境厌恶性地图，进而用于指导行为。然而，这些观察结果本质上主要是相关的。在此更新应用中，我们建议直接测试以下假设：vHPC 和 BLA 通过彼此之间以及与 mPFC 的相互作用来驱动厌恶和焦虑相关行为的神经表征。我们将使用各种药理学、光遗传学和药物遗传学工具来沉默 vHPC 和/或 BLA，并结合体内神经生理学来探讨这些区域在 mPFC 内厌恶性和焦虑样行为的神经表征中的作用。与此同时，我们将使用新兴技术来沉默来自这些大脑区域和这些大脑区域之间的特定投射，以确定是否以及如何需要这些特定投射。这些实验将在野生型和 5-HT1AR KO 小鼠中进行，以测试它们与病理和生理焦虑机制的相关性。解决这些问题将阐明这些大脑结构调节焦虑样行为的机制，并可能有助于识别焦虑背后的特定连接和活动模式，为治疗干预提供新的功能目标。