Modeling CO2-evoked fear in mice: role of acid-sensing ion channels

描述（由申请人提供）：焦虑症是最常见的精神疾病，对美国人的健康造成了巨大的影响。目前的治疗方法往往不足，这表明需要更有效、更具体的治疗方法。临床研究已经确定，吸入二氧化碳会引发焦虑和恐慌发作，而患有焦虑症的患者对二氧化碳的反应非常敏感。这些发现表明，更好地了解二氧化碳敏感性的分子机制可能会导致对焦虑症原因的新见解，并可能导致更好的治疗方法。由于对二氧化碳敏感性的研究主要是在临床研究中进行的，这些研究在确定分子机制方面受到限制，因此迫切需要动物模型来探索二氧化碳敏感性的潜在机制。在本提案中，我们通过模拟小鼠的二氧化碳行为和生理反应来解决二氧化碳诱发恐惧的动物模型的需求。我们研究了二氧化碳吸入降低大脑pH值的假设，这激活了恐惧回路中的pH敏感受体，从而增加了恐惧、焦虑和恐慌的行为和生理表现。这个项目可能对帮助解释长期以来公认的，但知之甚少的二氧化碳敏感性临床现象至关重要。此外，这些研究可能会产生更广泛的影响。我们的初步数据表明，二氧化碳激活了焦虑障碍的新信号通路，这些通路可能是治疗目标，以预防焦虑障碍并减轻其症状。公共卫生相关性：虽然已经确定二氧化碳（CO2）吸入会引发焦虑症患者的焦虑和恐慌，但其潜在机制尚不清楚。该研究建立了小鼠二氧化碳诱发的焦虑和恐慌模型，表明理解二氧化碳敏感性具有广泛的意义，包括焦虑障碍的新分子途径和新的治疗靶点。

DESCRIPTION (provided by applicant): Anxiety disorders are the most common form of psychiatric illness and exact a huge toll on America's health. Current treatments are often inadequate suggesting more effective, more specific therapies are needed. Clinical studies have firmly established that CO2 inhalation triggers anxiety and panic attacks, and that patients with anxiety disorders are hyper-responsive to CO2. These findings suggest that a better understanding of the molecular mechanisms underlying CO2 sensitivity could lead to novel insight into the causes of anxiety disorders and possibly lead to better treatments. Because CO2 sensitivity has been explored primarily in clinical studies, which are restricted in their ability to identify molecular mechanisms, there is a significant need for animal models to probe the mechanisms underlying CO2 sensitivity. In this proposal we address this need for animal models of CO2-evoked fear, by modeling CO2 behavioral and physiological responses in mice. We investigate the hypothesis that CO2 inhalation lowers brain pH, which activates pH-sensitive receptors in the fear circuit, which in turn increase the behavioral and physiological manifestations of fear, anxiety, and panic. This project may be critical for helping to explain the long recognized, but poorly understood clinical phenomenon of CO2 sensitivity. In addition, these studies are likely to have broader implications. Our preliminary data suggest that CO2 activates novel signaling pathways underlying anxiety disorders, and that these pathways might be therapeutically targeted to prevent anxiety disorders and reduce their symptoms. PUBLIC HEALTH RELEVANCE: Although it is well established that carbon dioxide (CO2) inhalation triggers anxiety and panic in anxiety disorder patients, the underlying mechanisms are not known. This proposal models CO2- evoked anxiety and panic in mice and suggests that understanding CO2-sensitivity has broad implications, including novel molecular pathways underlying anxiety disorders and new treatment targets.