Neuroimmune Factors and Co-Morbid Fear, Depression and Alcohol Consumption

神经免疫因素和共病恐惧、抑郁和饮酒

基本信息

项目摘要

DESCRIPTION (provided by applicant): Following exposure to traumatic stress individuals often go on to develop Post-Traumatic Stress Disorder (PTSD), which is characterized by enhanced anxiety to reminders of the trauma, nightmares, reliving the traumatic experience and a propensity to acquire new fears. PTSD is characterized by excessive drinking, anxiety, and depression that lasts for a prolonged period after the initial trauma. The result is that PTSD has a significant impact on the lives of individuals as well as on society as a whole. One challenge is to find the common link between stress-induced changes in anxiety, alcohol intake and depression. Considerable data suggest that neuroimmune factors may be that link. Once thought to be merely the packing peanuts of the brain, glial cells in the brain and spinal cord are integral to the proper functioning, signaling, and neuronal reparation in the brain. Microglia specifically are involved in neuroinflammation, which is associated with destructive chronic neuroimmune response. Activation of microgila produces pro-inflammatory cytokines. Increases in levels of pro-inflammatory cytokines are observed in PTSD, and major depressive disorder (MDD). Microglia as well as pro-inflammatory cytokines are increased in the brains of alcoholics. Thus, neuroimmune factors lay at a nexus of PTSD, depression and alcoholism. It is not known what mediates these long-term stress-induced changes, but stress can produce a neuroimmune response that significantly alters behavior. To address this challenge, we have assembled a team with demonstrated expertise in emotion related behavior (Fanselow), stress-induced neuroimmune function (Bradesi & Mayer), and the neurobiology of alcohol (Spigelman). Using a behavioral model of PTSD, our aims are to determine if stress is associated with a neuroimmune response within the amygdala and to determine if this response predicts changes in behavior, as well as determine if blockade of glia activation/neuroimmune response will reverse the behavioral sequelae of stress. Preliminary data with this stress model indicates exaggerated reactions to novel startling stimuli, increased anxiety and enhanced learning of new fears, which persist at least 3 months after stress without diminution. The same stress increased voluntary alcohol consumption relative to an unstressed control group. The model also produces prolonged alterations in gene expression patterns in the amygdala with up-regulation of several genes related to cytokines. Although stress-induced activation of central nervous system pro- inflammatory responses have been reported, there are significant gaps in knowledge about how they contribute to long term emotional disturbances and influence the amygdala. PUBLIC HEALTH RELEVANCE: Post-Traumatic Stress Disorder is characterized by excessive drinking, anxiety, and depression that develop and last for a prolonged period after the initial trauma. We will test the hypothesis that neuroimmune factors, such as cytokines and chemokines released in the CNS that are activated by stress mediate these long-lasting changes in behavior by acting like neurotransmitters, neuromodulators, or neurohormones in the brain. We will also determine if pharmacologically interfering with these neuroimmune pathways mitigate the symptoms of PTSD.
描述(由申请人提供):经历创伤性应激后,个体通常会发展为创伤后应激障碍(PTSD),其特征是对创伤、噩梦、重温创伤经历的焦虑感增强以及产生新的恐惧的倾向。创伤后应激障碍(PTSD)的特点是过度饮酒、焦虑和抑郁,这些症状在最初的创伤后持续很长一段时间。结果是创伤后应激障碍对个人的生活以及整个社会都有重大影响。一项挑战是找到压力引起的焦虑、饮酒和抑郁变化之间的共同联系。大量数据表明,神经免疫因素可能是其中的联系。大脑和脊髓中的神经胶质细胞曾经被认为只是大脑的包装花生,但它们对于大脑的正常功能、信号传导和神经元修复至关重要。小胶质细胞特别参与神经炎症,这与破坏性的慢性神经免疫反应有关。小胶质细胞的激活会产生促炎细胞因子。在创伤后应激障碍 (PTSD) 和重度抑郁症 (MDD) 中观察到促炎细胞因子水平升高。酗酒者大脑中的小胶质细胞和促炎细胞因子都会增加。因此,神经免疫因素与创伤后应激障碍、抑郁症和酗酒有关。目前尚不清楚是什么介导了这些长期压力引起的变化,但压力可以产生神经免疫反应,从而显着改变行为。为了应对这一挑战,我们组建了一支在情绪相关行为 (Fanselow)、压力诱发的神经免疫功能 (Bradesi & Mayer) 和酒精神经生物学 (Spigelman) 方面拥有丰富专业知识的团队。使用创伤后应激障碍(PTSD)的行为模型,我们的目的是确定压力是否与杏仁核内的神经免疫反应有关,并确定这种反应是否预测行为的变化,以及确定神经胶质细胞激活/神经免疫反应的阻断是否会逆转压力的行为后遗症。该压力模型的初步数据表明,人们对新的令人震惊的刺激反应过度,焦虑增加,对新恐惧的学习能力增强,这种情况在压力后至少持续 3 个月而不减弱。与无压力的对照组相比,相同的压力会增加自愿饮酒量。该模型还导致杏仁核基因表达模式发生长期改变,并上调与细胞因子相关的几个基因。尽管已经报道了压力诱导的中枢神经系统促炎症反应的激活,但对于它们如何导致长期情绪障碍和影响杏仁核,人们的认识还存在很大差距。 公共卫生相关性:创伤后应激障碍的特点是过度饮酒、焦虑和抑郁,这些症状在最初的创伤后发展并持续很长一段时间。我们将检验这样的假设:神经免疫因子,例如中枢神经系统中释放的细胞因子和趋化因子,在压力下被激活,通过像大脑中的神经递质、神经调节剂或神经激素一样介导这些持久的行为变化。我们还将确定药物干扰这些神经免疫途径是否可以减轻 PTSD 的症状。

项目成果

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Michael S Fanselow其他文献

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress
急性创伤应激所致恐惧敏感化的诱导与表达
  • DOI:
    10.1038/npp.2015.224
  • 发表时间:
    2015-08-06
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Jennifer N Perusini;Edward M Meyer;Virginia A Long;Vinuta Rau;Nathaniel Nocera;Jacob Avershal;James Maksymetz;Igor Spigelman;Michael S Fanselow
  • 通讯作者:
    Michael S Fanselow

Michael S Fanselow的其他文献

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{{ truncateString('Michael S Fanselow', 18)}}的其他基金

Mechanisms of enhanced synaptic drive in basolateral amygdala following stress
应激后基底外侧杏仁核突触驱动增强的机制
  • 批准号:
    10723781
  • 财政年份:
    2023
  • 资助金额:
    $ 47.27万
  • 项目类别:
Acute vs Chronic Stress-Enhanced Fear Learning
急性与慢性压力增强的恐惧学习
  • 批准号:
    10368978
  • 财政年份:
    2018
  • 资助金额:
    $ 47.27万
  • 项目类别:
Heterogeneity in Stress Effects on Fear Learning, Ethanol Consumption and Anxiety
压力对恐惧学习、乙醇消耗和焦虑影响的异质性
  • 批准号:
    9977941
  • 财政年份:
    2017
  • 资助金额:
    $ 47.27万
  • 项目类别:
Heterogeneity in Stress Effects on Fear Learning, Ethanol Consumption and Anxiety
压力对恐惧学习、乙醇消耗和焦虑影响的异质性
  • 批准号:
    9484109
  • 财政年份:
    2017
  • 资助金额:
    $ 47.27万
  • 项目类别:
Heterogeneity in Stress Effects on Fear Learning, Ethanol Consumption and Anxiety
压力对恐惧学习、乙醇消耗和焦虑影响的异质性
  • 批准号:
    10219943
  • 财政年份:
    2017
  • 资助金额:
    $ 47.27万
  • 项目类别:
Heterogeneity in Stress Effects on Fear Learning, Ethanol Consumption and Anxiety
压力对恐惧学习、乙醇消耗和焦虑影响的异质性
  • 批准号:
    9750570
  • 财政年份:
    2017
  • 资助金额:
    $ 47.27万
  • 项目类别:
PACAP Signaling in Fear Circuitries Relevant to Post-Traumatic Stress Disorder
与创伤后应激障碍相关的恐惧回路中的 PACAP 信号传导
  • 批准号:
    8600320
  • 财政年份:
    2012
  • 资助金额:
    $ 47.27万
  • 项目类别:
PACAP Signaling in Fear Circuitries Relevant to Post-Traumatic Stress Disorder
与创伤后应激障碍相关的恐惧回路中的 PACAP 信号传导
  • 批准号:
    8463349
  • 财政年份:
    2012
  • 资助金额:
    $ 47.27万
  • 项目类别:
Complete Fear Conditioning Suite for Rats and Mice
大鼠和小鼠的完整恐惧调节套件
  • 批准号:
    7794560
  • 财政年份:
    2010
  • 资助金额:
    $ 47.27万
  • 项目类别:
Neuroimmune Factors and Co-Morbid Fear, Depression and Alcohol Consumption
神经免疫因素和共病恐惧、抑郁和饮酒
  • 批准号:
    7810977
  • 财政年份:
    2009
  • 资助金额:
    $ 47.27万
  • 项目类别:

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