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。目前的治疗方法往往不足，表明需要更有效、更具体的治疗方法。临床研究已经证实，吸入二氧化碳会引发焦虑和惊恐发作，并且患有焦虑症的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背后的分子机制可能会带来对焦虑症原因的新见解，并可能带来更好的治疗方法。由于二氧化碳敏感性主要在临床研究中进行探索，而临床研究的分子机制识别能力受到限制，因此非常需要动物模型来探讨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满足对二氧化碳引起的恐惧动物模型的需求。我们研究了这样的假设：吸入二氧化碳会降低大脑 pH 值，从而激活恐惧回路中的 pH 敏感受体，进而增加恐惧、焦虑和恐慌的行为和生理表现。该项目对于帮助解释长期以来被认可但知之甚少的二氧化碳敏感性临床现象可能至关重要。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症背后的新信号通路，这些通路可能是治疗目标，以预防焦虑症并减轻其症状。

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.