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巨大损失。目前的治疗往往是不够的，这表明需要更有效，更具体的治疗。临床研究已经确定，二氧化碳吸入会引发焦虑和恐慌发作，焦虑症患者对二氧化碳反应过度。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。由于CO2敏感性主要在临床研究中探索，这些研究在识别分子机制的能力方面受到限制，因此非常需要动物模型来探索CO2敏感性的潜在机制。在这项提案中，我们解决了这种需要的CO2诱发的恐惧的动物模型，通过模拟CO2在小鼠的行为和生理反应。我们研究的假设是，二氧化碳吸入降低大脑pH值，激活恐惧回路中的pH敏感受体，这反过来又增加了恐惧，焦虑和恐慌的行为和生理表现。这个项目可能是至关重要的，有助于解释长期公认的，但了解甚少的临床现象的二氧化碳敏感性。此外，这些研究可能具有更广泛的影响。我们的初步数据表明，CO2激活了焦虑症潜在的新信号通路，这些通路可能是治疗靶点，以预防焦虑症并减轻其症状。公共卫生相关性：虽然二氧化碳（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。该提案模拟了小鼠中CO2诱发的焦虑和恐慌，并表明理解CO2敏感性具有广泛的意义，包括焦虑症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.