Hippocampal-dependent neural immune interactions regulate heroin withdrawal and future enhanced fear learning

海马依赖性神经免疫相互作用调节海洛因戒断和未来增强的恐惧学习

基本信息

  • 批准号:
    10362557
  • 负责人:
  • 金额:
    $ 1.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2022-05-08
  • 项目状态:
    已结题

项目摘要

Project Summary Opioid use disorder is a national crisis, and multiple lines of evidence indicate that heroin use leads to increased incidence and severity of anxiety disorders, including post-traumatic stress disorder (PTSD). Our laboratory has established a preclinical model that effectively demonstrates heroin withdrawal-induced hyperreactivity to future stressors, one of the key components of human PTSD. We discovered that withdrawal from escalating heroin administration results in an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and blockade of DH IL-1 with receptor antagonist (IL-1RA) prevents heroin withdrawal enhanced fear learning. This IL-1β is expressed predominantly in astrocytes, and heroin withdrawal also upregulates glial fibrillary acidic protein (GFAP) expression, a marker for astrocyte reactivity. This suggests that astrocyte signaling may be involved in heroin withdrawal and future enhanced fear learning, however it is presently unknown whether there is a causal link between the two. The current proposal is a targeted approach to test the overall hypothesis that heroin withdrawal enhances fear learning through DH astrocyte signaling and alterations in astrocyte physiology. Aim 1 tests the hypothesis that DH astrocytes mediate heroin withdrawal-induced enhanced fear learning. We have successfully implemented Gi-coupled designer receptors exclusively activated by designer drugs (Gi-DREADDs) into our research program to manipulate the DH astrocyte signaling in vivo. Aim 1 tests if astroglial GPCR signaling is capable of influencing the long-term effects of heroin withdrawal on enhanced fear learning. In Aim 1, I will be trained in chemogenetic techniques, acquire extensive knowledge of this cutting-edge tool, and become proficient in using glial DREADDs to investigate how astrocyte signaling relates to behavior. Results will establish that DH astroglial signaling during heroin withdrawal mediates changes in the development of long- term fear. Aim 2 tests the hypothesis that heroin withdrawal alters DH astrocyte morphology and astrocyte- neuron interactions. We have established a method to analyze the complexity of individual astrocytes using the AAV5-GFAP-Lck-GFP construct, high-resolution confocal microscopy, and advanced analysis of 3-dimensional cellular reconstructions. Using this innovative technique, we will examine the effect of heroin withdrawal on astrocyte morphology and colocalization with post synaptic markers, a proxy for astrocyte-neuron interactions. In Aim 2, I will refine and enhance my skills in IHC, confocal microscopy, and advanced cellular analysis using the Bitplane Imaris software to quantify withdrawal-induced changes in astrocyte morphology and synaptic interactions. Results will establish that heroin use and withdrawal directly alters DH astrocyte physiology that may lead to enhanced fear learning and anxiety. Collectively, this proposal examines the role of hippocampal astrocytes in mediating enhanced fear learning following heroin withdrawal. These studies make important contributions to understanding the effects of heroin withdrawal on astrocytes and provide a valuable learning experience to foster the independence of my research career in addiction neurobiology.
项目摘要 阿片类药物使用障碍是一个国家危机,多方面的证据表明,海洛因的使用导致增加 焦虑症的发病率和严重程度,包括创伤后应激障碍(PTSD)。本实验室 建立了一个临床前模型,有效地证明了海洛因戒断诱导的高反应性, 压力源,人类创伤后应激障碍的关键组成部分之一。我们发现从不断增加的海洛因中戒断 给药导致背海马(DH)白细胞介素-1 β(IL-1β)增加,并阻断DH IL-1 β 与受体拮抗剂(IL-1 RA)预防海洛因戒断增强恐惧学习。这种IL-1β表达于 主要在星形胶质细胞,海洛因戒断也上调胶质细胞酸性蛋白(GFAP) 表达,星形胶质细胞反应性的标志物。这表明星形胶质细胞信号可能与海洛因有关 退缩和未来增强恐惧学习,但目前尚不清楚是否有因果关系 两人之间目前的建议是一种有针对性的方法,以测试海洛因戒断的总体假设, 通过DH星形胶质细胞信号传导和星形胶质细胞生理学的改变增强恐惧学习。目标1测试 假设DH星形胶质细胞介导海洛因戒断诱导的恐惧学习增强。我们已经成功 将由设计药物专门激活的Gi偶联设计受体(Gi-DREADD)实施到我们的 在体内操纵DH星形胶质细胞信号传导的研究计划。Aim 1测试星形胶质细胞GPCR信号是否 能够影响海洛因戒断对增强恐惧学习的长期影响。在目标1中,我将 接受化学遗传学技术培训,获得这一尖端工具的广泛知识,并成为 擅长使用神经胶质DREADD研究星形胶质细胞信号与行为的关系。结果将 确定海洛因戒断期间DH星形胶质细胞信号传导介导长- 术语恐惧。目的2检验海洛因戒断改变DH星形胶质细胞形态和星形胶质细胞- 神经元相互作用我们已经建立了一种方法来分析单个星形胶质细胞的复杂性, AAV 5-GFAP-Lck-GFP构建体,高分辨率共聚焦显微镜,以及三维的高级分析 细胞重建使用这种创新的技术,我们将研究海洛因戒断对 星形胶质细胞形态和与突触后标记物的共定位,星形胶质细胞-神经元相互作用的代表。 在目标2中,我将使用免疫组化,共聚焦显微镜和高级细胞分析来完善和提高我的技能。 Bitplane Imaris软件定量戒断诱导星形胶质细胞形态和突触 交互.结果将确定海洛因的使用和戒断直接改变DH星形胶质细胞的生理学, 可能会导致恐惧学习和焦虑的增强。总的来说,这项建议探讨了海马的作用, 星形胶质细胞介导海洛因戒断后增强的恐惧学习。这些研究使得 有助于了解海洛因戒断对星形胶质细胞的影响,并提供了一个有价值的学习 我的经验,以促进我在成瘾神经生物学的研究生涯的独立性。

项目成果

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