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

模拟二氧化碳引起的小鼠恐惧：酸敏感离子通道的作用

• 批准号: 7806551
• 负责人: John A Wemmie
• 金额: $ 37.24万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-16 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806551
• 关键词: ASIC channel; Acidosis; Acids; Address; Americas; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Area; Attenuated; Behavior; Behavioral; Bicarbonates; Biological Markers; Brain; Breathing; Carbon Dioxide; Cardiovascular system; Chemicals; Clinical; Clinical Research; Complex; Data; Fostering; Freezing; Fright; Health; Human; Hydration status; Invertebrates; Kinetics; Lead; Mammals; Mediating; Microinjections; Modeling; Molecular; Mus; Neurobiology; Neurons; Neurotransmitters; Panic; Panic Attack; Pathway interactions; Patients; Physiological; Protons; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Structure; Structure of terminal stria nuclei of preoptic region; Symptoms; Synapses; Testing; Therapeutic; Transgenic Mice; Translating; Viral Vector; carbonate dehydratase; chemical reaction; conditioned fear; insight; midbrain central gray substance; novel; novel therapeutics; overexpression; prevent; public health relevance; receptor; relating to nervous system; research study; response

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.

描述（由申请人提供）：焦虑症是精神病的最常见形式，对美国健康造成了巨大损失。当前的治疗通常不足以表明需要更有效，需要更具体的疗法。临床研究已经牢固地确定二氧化碳吸入会引发焦虑和惊恐发作，并且焦虑症患者对CO2具有超反应性。这些发现表明，对二氧化碳敏感性的分子机制有更好的了解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。由于二氧化碳灵敏度主要是在临床研究中探索的，这些研究受到识别分子机制的能力受到限制，因此动物模型非常需要探测CO2敏感性的机制。在此提案中，我们通过对小鼠的二氧化碳行为和生理反应进行建模，以解决对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脑pH的假设，该二氧化碳在恐惧回路中激活了pH敏感的受体，进而增加了恐惧，焦虑和恐慌的行为和生理表现。该项目对于帮助解释二氧化碳敏感性的临床现象的长期以来的临床现象可能至关重要。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，二氧化碳激活了焦虑症的新型信号通路，并且这些途径可能是治疗目标以防止焦虑症并减轻症状的目标。公共卫生相关性：尽管尚未确定二氧化碳（CO2）吸入引发焦虑症患者的焦虑和恐慌，但尚不清楚基本机制。该提议模型在小鼠中引起了焦虑和恐慌，并建议理解二氧化碳敏感性具有广泛的影响，包括焦虑症的基本分子途径和新的治疗靶标。