Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments

心理压力降低内源性大麻素张力:机制和可能的治疗方法

基本信息

项目摘要

One debilitating mental health problem among veterans is post-traumatic stress disorder (PTSD), which is an anxiety disorder (PTSD) and develops following the experience of life- threatening psychological trauma. Individuals with PTSD have reduced circulating levels of endocannabinoids (eCB) including 2-AG. Since disruption of 2-AG signaling leads to mood disorders, impaired memory extinction and enhanced pain, the ability to reverse the stress- induced change in 2-AG production/degradation holds great potential for the treatment of PTSD. Given the importance of 2-AG signaling in the stress response and associative fear learning, an understanding of how stress produces a lasting decrease in 2-AG levels is needed to bridge the knowledge gap that exists between traumatic stress and the associated reduction in 2-AG content. Exposure of rodents to natural predator odors causes psychological stress, leading to enhanced associative fear learning and thus has been used to model several aspects of PTSD. We have previously shown that fox urine exposure produced a lasting increase in excitatory synaptic transmission via the activation of adrenergic receptors in the mouse cerebellum. This brain region is required for the innate response to predator odor and for the consolidation of fear memory. Our pilot data show that predator odor exposure reduced 2-AG signaling in the cerebellum and this stressor abolished A-type K currents in inhibitory interneurons. Therefore our central hypothesis is that predator odor stress enhances excitability of GABAergic interneurons and thereby reduces 2-AG signaling, thus pharmacological interventions that inhibit 2-AG degradation and reduce neuronal excitability would reverse the stress-induced decrease in 2-AG levels. In Aim 1, we will determine whether a psychological stress reduces 2- AG tone by increasing 2-AG degradation or by reducing 2-AG production. Aim 2 will test the hypothesis that emotional stress reduces 2-AG signaling by increasing inhibitory interneuron activity. We will test whether several FDA approved drugs that reduce neuronal activity can reverse the stress-induced change. Because the proposed study investigates a new mechanism underlying the regulation of 2-AG metabolism by psychological stress, it could suggest novel treatment strategies for PTSD and new therapeutic targets.
退伍军人中一个令人衰弱的心理健康问题是创伤后应激障碍 创伤后应激障碍(PTSD),这是一种焦虑症(PTSD),并发展以下的生活经验- 可能造成心理创伤患有PTSD的人循环中的 内源性大麻素(eCB),包括2-AG。由于2-AG信号的中断导致情绪 障碍,记忆力减退和疼痛加剧,逆转压力的能力- 诱导的2-AG产生/降解的变化对于治疗PTSD具有很大的潜力。 鉴于2-AG信号在应激反应和联想恐惧学习中的重要性, 需要了解压力如何导致2-AG水平持续下降, 创伤应激和相关的2-AG减少之间存在的知识差距 内容啮齿动物暴露于自然捕食者的气味会引起心理压力,导致 增强的联想恐惧学习,因此已被用于模拟创伤后应激障碍的几个方面。 我们先前已经表明,狐狸尿暴露产生了持久的兴奋性增加, 通过激活小鼠小脑中的肾上腺素能受体的突触传递。这 对捕食者气味的先天反应和恐惧的巩固需要大脑区域 记忆我们的试验数据表明,捕食者的气味暴露减少了2-AG信号, 小脑和这种应激废除了抑制性中间神经元的A型K电流。因此 我们的中心假设是捕食者气味应激增强GABA能神经元的兴奋性, 从而减少2-AG信号传导,因此药理学干预, 抑制2-AG降解和降低神经元兴奋性将逆转应激诱导的 2-AG水平下降。在目标1中,我们将确定心理压力是否会降低2- 通过增加2-AG降解或减少2-AG产生来调节AG。目标2将测试 情绪应激通过增加抑制性中间神经元而减少2-AG信号传导的假说 活动我们将测试几种FDA批准的减少神经元活动的药物是否能 扭转压力引起的变化。因为这项研究调查了一种新的机制, 作为心理应激对2-AG代谢调节的基础,它可能提示新的 PTSD的治疗策略和新的治疗靶点。

项目成果

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Siqiong June Liu其他文献

phenotype in mouse cerebellar stellate cells channel activity alters synaptic AMPA receptor + -activated large-conductance K 2+ Inhibition of Ca
小鼠小脑星状细胞表型通道活性改变突触 AMPA 受体激活的大电导 K 2 抑制 Ca
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    J. Savtchouk;S. Acharjee;Siqiong June Liu
  • 通讯作者:
    Siqiong June Liu
Emotional stress increases GluA2 expression and potentiates fear memory via adenylyl cyclase 5
情绪应激通过腺苷酸环化酶 5 增加 GluA2 表达并增强恐惧记忆。
  • DOI:
    10.1016/j.celrep.2024.115180
  • 发表时间:
    2025-01-28
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Qian Yang;Ahmad Abdulla;Muhammad Farooq;Yoshihiro Ishikawa;Siqiong June Liu
  • 通讯作者:
    Siqiong June Liu
Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells123
Alexa Fluor 488 和 594 对小脑星状细胞中 AMPA 受体介导的突触传递的改变123
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Matthieu Maroteaux;Siqiong June Liu
  • 通讯作者:
    Siqiong June Liu
Stellate Cells: Synaptic Processing and Plasticity
星状细胞:突触处理和可塑性
HippocampusSynapses in Area CA3 of the Mouse Y5 Receptors Mediate Neuropeptide Y Actions at
小鼠 Y5 受体 CA3 区的海马突触介导神经肽 Y 的作用
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    P. A. Castro;R. Palmiter;S. Baraban;C. Dubois;P. Ramamoorthy;M. Whim;Siqiong June Liu;B. Beck;G. Pourié
  • 通讯作者:
    G. Pourié

Siqiong June Liu的其他文献

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{{ truncateString('Siqiong June Liu', 18)}}的其他基金

Activity-dependent degradation of a neuromodulator
神经调节剂的活性依赖性降解
  • 批准号:
    10651741
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Activity-dependent degradation of a neuromodulator
神经调节剂的活性依赖性降解
  • 批准号:
    10460492
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Activity-dependent degradation of a neuromodulator
神经调节剂的活性依赖性降解
  • 批准号:
    10189725
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
  • 批准号:
    10292952
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
  • 批准号:
    10046274
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
  • 批准号:
    10616660
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
  • 批准号:
    8446283
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
  • 批准号:
    9027880
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
  • 批准号:
    8297527
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
  • 批准号:
    8826180
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
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