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: 8391587
• 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/8391587
• 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.

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，但令人失望的是，大量患者对目前的治疗方法无效，所有这些治疗方法都针对类似的机制。因此，迫切需要具有新作用机制的新药。利用可以预测人类抗抑郁和抗焦虑效果的动物模型，我们发现了一种与抑郁和焦虑相关的行为中的新分子，即酸感应离子通道1a(ASIC1a)。在小鼠的强迫游泳试验、尾部悬吊试验和慢性不可预测的应激反应中，药物抑制和遗传干扰ASIC1a产生了抗抑郁药样作用。此外，这些作用独立于目前使用的几种抗抑郁药物，并与之相加。扰乱ASIC1a还可以减少条件性和非条件性恐惧行为，这些行为会导致创伤后应激障碍(PTSD)和其他焦虑症。总而言之，这些发现表明，靶向ASIC1a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ASIC1a是如何在大脑中激活的。ASIC1a对低细胞外pH的敏感度表明，酸性pH可能起着重要的信号作用。我们假设，情绪痛苦刺激会降低杏仁核的pH值，进而激活ASIC1a，促进包括抑郁和焦虑相关行为在内的应激反应。为了验证这一假设，我们建议回答以下问题：1)操纵ASIC1a的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亚单位的表达是否会影响抑郁相关行为？并且，3)PH值可以作为治疗的靶点来减轻抑郁吗？我们计划中的实验利用了最近的几项进展，包括：我们使用光纤pH传感器测量行为小鼠大脑pH的能力，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依赖的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，这些机会可能会迅速转化为人类研究和治疗。例如，许多技术可以被用来安全地改变人类大脑的pH值，并可能被用来干预抑郁症和严重情绪压力的其他精神后果。