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

• 批准号: 8667500
• 负责人: Joshua A Gordon
• 金额: $ 39.74万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667500
• 关键词: Address; Adult; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Brain; Brain region; Cell Nucleus; Data; Development; Disease; Emerging Technologies; Emotional; 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; Pattern; Pharmacogenetics; Phenotype; Physiological; Prefrontal Cortex; Property; Public Health; Regulation; Role; Serotonin Receptor 5-HT1A; Societies; Staging; Structure; System; Techniques; Testing; Therapeutic Intervention; Work; avoidance behavior; cost; in vivo; innovation; interest; neural patterning; neurobiological mechanism; neurophysiology; novel; novel strategies; optogenetics; public health relevance; relating to nervous system; research study; tool

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）：当前的建议旨在了解焦虑症的神经生物学机制。促进对焦虑症的理解仍然是一个关键的未满足的公共卫生目标，因为这些疾病代表了社会在发病率和相关成本方面的巨大负担。我们先前对野生型和5-羟色胺1A-受体敲除（5-HT1AR KO）小鼠的研究暗示了由腹侧海马（VHPC）组成的电路，基底外侧杏仁核（BLA）和内侧前额叶额叶皮质（MPFC）对各种焦虑般的焦虑型行为。最值得注意的是，我们已经表明，这三个区域在焦虑期间功能相互作用，并且这些相互作用的强度（1）与焦虑相关，而在高度焦虑的5- HT1AR KO小鼠中，（2）比野生型同窝仔相比。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的地图，而环境的厌恶性又用于指导行为。但是，这些观察结果本质上主要是相关的。在此续订应用中，我们建议直接检验以下假设：VHPC和BLA通过彼此的相互作用以及与MPFC的相互作用来驱动厌恶性和与焦虑相关的行为的神经表示。我们将使用各种药理，光学遗传学和药物遗传学工具来使VHPC和/或BLA保持沉默，并结合体内神经生理学，以探测这些区域在MPFC内厌恶性神经表示中的作用以及焦虑般的行为。同时，我们将使用旨在使这些大脑区域和之间的特定预测沉默的新兴技术来确定是否需要这些特定的预测。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类似焦虑的行为的机制，并可能有助于确定与焦虑的连通性和活动模式，从而为治疗干预提供了新颖的功能靶标。