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

描述（由申请人提供）：目前的提案旨在了解焦虑障碍的神经生物学机制。进一步了解焦虑症仍然是一个关键的未实现的公共卫生目标，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5-羟色胺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）和内侧前额叶皮质（mPFC）组成的回路在各种范式下调节焦虑样行为。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相互作用，并且这些相互作用的强度(1)与焦虑相关，(2)在高度焦虑的5- HT1AR KO小鼠中比在野生型小鼠中更大。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度的地图，这反过来又用于指导行为。然而，这些观察结果在本质上主要是相关的。在这个更新的应用中，我们建议直接检验vHPC和BLA通过相互作用和与mPFC的相互作用驱动厌恶和焦虑相关行为的神经表征的假设。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索这些区域在mPFC内厌恶的神经表征以及焦虑样行为中的作用。与此同时，我们将使用新兴的技术，旨在沉默来自这些大脑区域和之间的特定投射，以确定这些特定的投射是否以及如何被需要。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。解决这些问题将澄清这些大脑结构调节焦虑样行为的机制，并可能有助于确定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靶点。

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.