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

基本信息

批准号：
7633101
负责人：
John A Wemmie
金额：
$ 37.25万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/7633101
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

项目摘要

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。公共卫生相关性：虽然众所周知，吸入二氧化碳 (CO2) 会引发焦虑症患者的焦虑和恐慌，但其潜在机制尚不清楚。该提案模拟了二氧化碳引起的小鼠焦虑和恐慌，并表明了解二氧化碳敏感性具有广泛的意义，包括焦虑症背后的新分子途径和新的治疗目标。