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

基本信息

  • 批准号:
    7929354
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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):

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

John A Wemmie其他文献

John A Wemmie的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('John A Wemmie', 18)}}的其他基金

Novel mechanisms for correcting opioid-induced synaptic abnormalities
纠正阿片类药物引起的突触异常的新机制
  • 批准号:
    10610455
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Investigating a novel regulatory pathway for opioid-induced synaptic plasticity and behavior
研究阿片类药物诱导的突触可塑性和行为的新调控途径
  • 批准号:
    10516021
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Investigating a novel regulatory pathway for opioid-induced synaptic plasticity and behavior
研究阿片类药物诱导的突触可塑性和行为的新调控途径
  • 批准号:
    10292973
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Investigating a novel regulatory pathway for opioid-induced synaptic plasticity and behavior
研究阿片类药物诱导的突触可塑性和行为的新调控途径
  • 批准号:
    10066256
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Basolateral amygdala circuits in defensive behavior regulation
基底外侧杏仁核回路在防御行为调节中的作用
  • 批准号:
    10311537
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
ASICs in the n. accumbens in depression-related synaptic plasticity and behavior
n 中的 ASIC。
  • 批准号:
    8967085
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8196333
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8020063
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

相似国自然基金

具有抗癌活性的天然产物金霉酸(Aureolic acids)全合成与选择性构建2-脱氧糖苷键
  • 批准号:
    22007039
  • 批准年份:
    2020
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目
海洋放线菌来源聚酮类化合物Pteridic acids生物合成机制研究
  • 批准号:
  • 批准年份:
    2019
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
手性Lewis Acids催化的分子内串联1,5-氢迁移/环合反应及其在构建结构多样性手性含氮杂环化合物中的应用
  • 批准号:
    21372217
  • 批准年份:
    2013
  • 资助金额:
    80.0 万元
  • 项目类别:
    面上项目
对空气稳定的新型的有机金属Lewis Acids催化剂制备、表征与应用研究
  • 批准号:
    21172061
  • 批准年份:
    2011
  • 资助金额:
    30.0 万元
  • 项目类别:
    面上项目
钛及含钛Lewis acids促臭氧/过氧化氢体系氧化性能的广普性、高效性及其机制
  • 批准号:
    21176225
  • 批准年份:
    2011
  • 资助金额:
    60.0 万元
  • 项目类别:
    面上项目
基于Zip Nucleic Acids引物对高度降解和低拷贝DNA检材的STR分型研究
  • 批准号:
    81072511
  • 批准年份:
    2010
  • 资助金额:
    31.0 万元
  • 项目类别:
    面上项目
海洋天然产物Makaluvic acids 的全合成及其对南海鱼虱存活的影响
  • 批准号:
    30660215
  • 批准年份:
    2006
  • 资助金额:
    21.0 万元
  • 项目类别:
    地区科学基金项目

相似海外基金

Lipid nanoparticle-mediated Inhalation delivery of anti-viral nucleic acids
脂质纳米颗粒介导的抗病毒核酸的吸入递送
  • 批准号:
    502577
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
CAREER: Highly Rapid and Sensitive Nanomechanoelectrical Detection of Nucleic Acids
职业:高度快速、灵敏的核酸纳米机电检测
  • 批准号:
    2338857
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Continuing Grant
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Synthetic analogues based on metabolites of omega-3 fatty acids protect mitochondria in aging hearts
基于 omega-3 脂肪酸代谢物的合成类似物可保护衰老心脏中的线粒体
  • 批准号:
    477891
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Operating Grants
Metabolomic profiles of responders and non-responders to an omega-3 fatty acids supplementation.
对 omega-3 脂肪酸补充剂有反应和无反应者的代谢组学特征。
  • 批准号:
    495594
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Integrated understanding and manipulation of hypoxic cellular functions by artificial nucleic acids with hypoxia-accumulating properties
具有缺氧累积特性的人工核酸对缺氧细胞功能的综合理解和操纵
  • 批准号:
    23H02086
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了