Determining astrocytic contributions to memory-related dimensions of PTSD

确定星形胶质细胞对 PTSD 记忆相关维度的贡献

基本信息

批准号：
10252235
负责人：
Brian George DIAS
金额：
$ 21.67万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252235
关键词：
Adult Affect Astrocytes Behavior Behavioral Brain Brain region Cells Chemicals Corticosterone Data Data Reporting Development Dimensions Drug Targeting Event Exposure to Extinction (Psychology)FDA approved Fright Functional disorder Future Glucocorticoid Receptor Goals Hormone Receptor Hormones Impairment Knock-out Learning Light Link Measures Mediating Memory Molecular Mus Nervous system structure Neuroglia Neurons Outcome Paroxetine Pathology Pathway interactions Pharmacological Treatment Play Population Post-Traumatic Stress Disorders Prefrontal Cortex Recording of previous events Risk Factors Role Sertraline Shock Signal Pathway Signal Transduction Stimulus Stress Testing Time Training Trauma Work biological adaptation to stress cell type cellular targeting conditioned fear fear memory knock-down learning extinction neuropsychiatric disorder neurotransmission notch protein novel novel therapeutic intervention novel therapeutics post-traumatic symptoms receptor expression receptor function transcription factor translational impact traumatic event

项目摘要

PROJECT SUMMARY Post Traumatic Stress Disorder (PTSD) is a devastating neuropsychiatric disorder that develops after trauma. A previous history of stress exposure significantly increases the likelihood of developing PTSD after a traumatic event. Deficits in extinction learning are a debilitating and core symptom of PTSD. This inability to learn that stimuli previously linked to trauma are no longer threatening causes maladaptive fear expression toward these stimuli. Efforts to reduce stress-induced deficits in extinction learning have included identifying stress-induced perturbations of molecular pathways in the brain. Most of this work has either treated brain regions as a homogeneous population of cells or mainly focused on neurons. While glia are the most populous cells in the nervous system, we have little appreciation for their contribution to stress-induced deficits in extinction learning. In this proposal, we examine how molecular events in astrocytes (the most predominant glial cell population) influence stress-induced deficits in extinction learning. More specifically, we study the relationship between astrocytes in the infra-limbic prefrontal cortex, a brain region important for extinction learning and stress-induced deficits in extinction learning. We hypothesize that in the adult brain, stress- induced deficits in extinction learning are, in part, mediated by stress hormone action and increased activity of developmental signaling pathways, in astrocytes of the infra-limbic prefrontal cortex. To test this hypothesis, we will study stress-induced deficits in extinction learning after manipulating stress hormone receptor function and the activity of developmental signaling cascades in astrocytes of the infra-limbic prefrontal cortex. Successful outcomes from our work will shed new light on how molecular function in astrocytes contribute to stress-induced impairments in extinction learning. Additionally, our work has the potential to recommend new cell-type specific molecular pathways that could be targeted to mitigate a highly prevalent and debilitating memory-related dimension of PTSD.

项目摘要创伤后应激障碍（PTSD）是一种毁灭性的神经精神疾病，在创伤。以前的压力暴露病史显着增加了在创伤事件。灭绝学习的缺陷是PTSD的衰弱和核心症状。这无力得知以前与创伤有关的刺激不再威胁到适应不良的恐惧表达朝向这些刺激。减少压力引起的灭绝学习缺陷的努力包括识别压力诱导的大脑分子途径的扰动。这项工作的大部分已经治疗了大脑区域作为均质细胞群，或主要集中于神经元。而神经胶质是人口最多的神经系统中的细胞，我们对它们对压力引起的缺陷的贡献几乎不明智灭绝学习。在此提案中，我们研究了星形胶质细胞中的分子事件如何（最主要的神经胶质细胞种群）影响压力引起的灭绝学习缺陷。更具体地说，我们研究在上边缘前额叶皮层中星形胶质细胞之间的关系，这对于灭绝很重要的大脑区域学习和压力引起的灭绝学习缺陷。我们假设在成人大脑中，应力 - 灭绝学习中诱发的缺陷部分是由压力激素作用和增加的活性介导的发育信号通路，在上皮前额叶皮层的星形胶质细胞中。为了检验这一假设，我们将研究处理应力激素受体功能后的压力引起的灭绝学习缺陷以及发育信号级联的活性在上边缘前额叶皮层的星形胶质细胞中。我们工作的成功结果将为星形胶质细胞中的分子功能有何贡献，从而有了新的启示压力引起的灭绝学习障碍。此外，我们的工作有可能推荐新的细胞类型的特定分子途径，可以针对缓解高度流行和衰弱 PTSD的内存相关维度。