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: 7929354
• 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/7929354
• 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; 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。抑郁症一直是发病率和死亡率最高的原因之一，退伍军人比非退伍军人更常见。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，但令人不安的是，大量患者对目前的治疗难以治疗，所有这些治疗都针对类似的机制。因此，迫切需要具有新作用机制的新药物。使用可以预测人类抗抑郁和抗焦虑作用的动物模型，我们确定了抑郁和焦虑相关行为的新分子，酸敏感离子通道1a（ASIC 1a）。药理学抑制和遗传破坏ASIC 1a在小鼠中产生抗抑郁样作用，在强迫游泳试验，悬尾试验，和以下慢性不可预测的压力。此外，这些作用独立于目前使用的几种抗抑郁药物，并与之叠加。破坏ASIC 1a还减少了条件性和非条件性恐惧行为，这是创伤后应激障碍（PTSD）和其他焦虑症的模型。这些发现表明，靶向ASIC 1a将通过一种新的作用机制缓解抑郁和焦虑的可能性令人兴奋。为了充分利用这种可能性，我们需要更多地了解ASIC 1a在大脑中是如何被激活的。ASIC 1a对低细胞外pH的敏感性表明酸性pH可能发挥重要的信号作用。我们假设，情绪上的痛苦刺激会降低杏仁核的pH值，从而激活ASIC 1a，促进压力反应，包括抑郁和焦虑相关的行为。为了验证这一假设，我们建议回答以下问题：1）操纵ASIC 1a pH敏感性是否会改变其对抑郁相关行为的影响？2)改变ASIC 1a和其他ASIC亚基的表达是否会影响抑郁相关行为？以及，3）pH值是否可以作为治疗目标来减少抑郁症？我们计划的实验利用了几项最新进展，包括：我们能够用光纤pH传感器测量行为小鼠的大脑pH值，以及我们能够改变ASIC 1a通道的pH敏感性并评估行为后果。如果pH依赖性信号导致抑郁和焦虑，那么操纵pH或ASIC可以提供新的治疗机会，可以迅速转化为人类研究和治疗。例如，许多技术可以用来安全地改变人类大脑的pH值，并可能用于干预抑郁症和严重情绪压力的其他精神疾病后果。 公共卫生相关性： 抑郁症是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其他人的两倍多。不幸的是，许多退伍军人对目前的药物没有反应。因此，迫切需要具有新作用机制的新治疗方法。使用可以预测人类抗抑郁疗效的动物模型，我们发现了一种新的离子通道，当被破坏或抑制时，在小鼠中产生抗抑郁和抗焦虑样作用。这种通道被称为酸敏感离子通道-1a（ASIC 1a），由酸性pH激活。这些通道的pH敏感性，加上大脑中pH波动与神经活动有关的证据，表明pH可能在大脑中发挥重要的信号作用，促进抑郁和焦虑。在这项提案中，我们将确定大脑pH值对ASIC 1a通道活性的贡献，并测试ASIC 1a和大脑pH值是否可以减少抑郁症。