Brain pH and Acid Sensing in Depression-Related Behavior

抑郁相关行为中的大脑 pH 值和酸感应

• 批准号: 8597367
• 负责人: John A Wemmie
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597367
• 关键词: ASIC channel; Acids; Affect; Amygdaloid structure; Animal Model; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological; Brain; Brain-Derived Neurotrophic Factor; Chronic; Clinical; Coupled; Custom; Dependovirus; Distress; Emotional Stress; Family; Fiber Optics; Fright; General Population; Hippocampus (Brain); Human; Invertebrates; Ion Channel; Kinetics; Knockout Mice; Learning; Measures; Mental Depression; Modeling; Morbidity - disease rate; Mus; Mutation; Neurons; Neurotransmitters; Patients; Pharmaceutical Preparations; Play; Post-Traumatic Stress Disorders; Protons; Refractory; Research; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Stimulus; Stress; Stress Tests; Suicide; Swimming; Symptoms; Synaptic plasticity; Tail Suspension; Techniques; Testing; Therapeutic; Transgenic Mice; Translating; Veterans; Work; abstracting; adeno-associated viral vector; behavior test; biological adaptation to stress; disability; epithelial Na+ channel; extracellular; in vivo; insight; member; mortality; mutant; novel; novel therapeutics; public health relevance; relating to nervous system; research study; response; sensor

DESCRIPTION (provided by applicant): Abstract. Depression is consistently one of the top causes of morbidity and mortality, and veterans are afflicted more commonly than non-veterans. In addition, veterans are more than twice likely to die from depression-related suicide than the general population. Despite current antidepressant medications, a disappointingly large number of patients are refractory to current treatments, all of which target similar mechanisms. Thus, new medications with novel mechanisms of action are urgently needed. Using animal models that can predict antidepressant and anti-anxiety effects in humans, we identified a novel molecule in depression and anxiety- related behaviors, the acid-sensing ion channel 1a (ASIC1a). Pharmacologically inhibiting and genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, tail suspension test, and following chronic unpredictable stress. Moreover, the effects were independent of and additive to several currently used antidepressant medications. Disrupting ASIC1a also reduced conditioned and unconditioned fear behaviors, which model post-traumatic stress disorder (PTSD) and other anxiety disorders. Together these findings suggest the exciting possibility that targeting ASIC1a will relieve depression and anxiety through a novel mechanism of action. To take full advantage of this possibility we need to know more about how ASIC1a is activated in the brain. The exquisite sensitivity of ASIC1a to low extracellular pH suggests that acidic pH might play an important signaling role. We hypothesize that emotionally distressing stimuli lower pH in the amygdala, which in turn activates ASIC1a to promote stress responses including depression and anxiety-related behaviors. To test this hypothesis we propose to answer the following questions: 1) Does manipulating ASIC1a pH sensitivity alter its effects on depression-related behavior? 2) Does altering the expression of ASIC1a and other ASIC subunits influence depression-related behavior? And, 3) can pH be therapeutically targeted to reduce depression? Our planned experiments take advantage of several recent advances including: our ability to measure brain pH in behaving mice with a fiber optic pH sensor, and our ability to alter the pH sensitivity of ASIC1a channels and assess the behavioral consequences. If pH dependent signaling contributes to depression and anxiety, then manipulating pH or ASICs could provide novel therapeutic opportunities that may be rapidly translated to human research and treatment. For example, a number of techniques can be used to safely alter human brain pH, and might be used to intervene in depression and in other psychiatric consequences of severe emotional stress. PUBLIC HEALTH RELEVANCE: Depression is a leading cause of disability and mortality that affects veterans even more frequently than non-veterans. Moreover, veterans are more than twice as likely to die from depression-related suicide. Unfortunately, a large number of veterans do not respond to current medications. Thus, new treatments with novel mechanisms of action are desperately needed. Using animal models that can predict antidepressant efficacy in humans, we found a novel ion channel that when disrupted or inhibited produces antidepressant and anti-anxiety-like effects in mice. This channel, called acid-sensing ion channel-1a (ASIC1a), is activated by acidic pH. The pH sensitivity of these channels, coupled with evidence that pH fluctuations occur in the brain with neural activity, suggests that pH might play an important signaling role in the brain to promote depression and anxiety. In this proposal, we will determine the contribution of brain pH to ASIC1a channel activity, and test whether ASIC1a and brain pH might be targeted to reduce depression.

描述（由申请人提供）： 抽象的。抑郁症一直是发病和死亡的主要原因之一，退伍军人比非退伍军人更容易受到抑郁症的困扰。此外，退伍军人死于抑郁症相关自杀的可能性是普通人群的两倍多。尽管目前有抗抑郁药物，但令人失望的是，仍有大量患者对当前的治疗有抵抗力，所有这些治疗都针对相似的机制。因此，迫切需要具有新颖作用机制的新药物。利用可以预测人类抗抑郁和抗焦虑作用的动物模型，我们发现了一种与抑郁和焦虑相关行为相关的新分子，即酸敏感离子通道 1a (ASIC1a)。对小鼠进行药理学抑制和基因破坏 ASIC1a，在强迫游泳试验、悬尾试验和慢性不可预测应激后产生抗抑郁样作用。此外，这些效果独立于目前使用的几种抗抑郁药物，并且与这些药物相辅相成。破坏 ASIC1a 还可以减少条件性和非条件性恐惧行为，这些行为模拟了创伤后应激障碍 (PTSD) 和其他焦虑症。这些发现共同表明，靶向 ASIC1a 将通过一种新颖的作用机制缓解抑郁和焦虑。为了充分利用这种可能性，我们需要更多地了解 ASIC1a 在大脑中是如何被激活的。 ASIC1a 对低细胞外 pH 值的高度敏感性表明酸性 pH 值可能发挥重要的信号作用。我们假设，令人痛苦的情绪刺激会降低杏仁核的 pH 值，进而激活 ASIC1a 来促进应激反应，包括抑郁和焦虑相关行为。为了检验这一假设，我们建议回答以下问题：1）操纵 ASIC1a pH 敏感性是否会改变其对抑郁相关行为的影响？ 2) 改变 ASIC1a 和其他 ASIC 亚基的表达是否会影响抑郁相关行为？并且，3）pH 值可以作为治疗目标来减少抑郁症吗？我们计划的实验利用了多项最新进展，包括：我们能够使用光纤 pH 传感器测量行为小鼠的大脑 pH 值，以及我们改变 ASIC1a 通道的 pH 敏感性并评估行为后果的能力。如果 pH 依赖性信号传导导致抑郁和焦虑，那么操纵 pH 或 ASIC 可以提供新的治疗机会，并可以快速转化为人类研究和治疗。例如，许多技术可用于安全地改变人脑 pH 值，并可用于干预抑郁症和严重情绪压力造成的其他精神后果。 公共卫生相关性： 抑郁症是导致残疾和死亡的主要原因，对退伍军人的影响甚至比非退伍军人更频繁。此外，退伍军人死于抑郁症相关自杀的可能性是退伍军人的两倍多。不幸的是，大量退伍军人对当前的药物没有反应。因此，迫切需要具有新颖作用机制的新疗法。利用可以预测人类抗抑郁功效的动物模型，我们发现了一种新型离子通道，当其被破坏或抑制时，会对小鼠产生抗抑郁和抗焦虑样作用。该通道称为酸敏感离子通道 1a (ASIC1a)，由酸性 pH 值激活。这些通道的 pH 敏感性，再加上大脑中随神经活动而发生 pH 值波动的证据，表明 pH 值可能在大脑中发挥重要的信号作用，从而促进抑郁和焦虑。在本提案中，我们将确定大脑 pH 值对 ASIC1a 通道活动的贡献，并测试 ASIC1a 和大脑 pH 值是否可能有助于减少抑郁症。