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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障碍，外伤先前的压力暴露史显着增加了在经历了一段时间的创伤后应激障碍后发展为创伤后应激障碍的可能性。创伤性事件消退学习的缺陷是PTSD的一个核心症状。这种无法了解到以前与创伤有关的刺激不再具有威胁性，会导致适应不良的恐惧表达对这些刺激。减少压力引起的灭绝学习缺陷的努力包括确定压力引起的脑内分子通路紊乱。大部分的研究都是针对大脑区域作为同质的细胞群体或主要集中在神经元上。虽然神经胶质细胞是数量最多的神经系统中的细胞，我们对它们在压力诱导的缺陷中的作用知之甚少。灭绝学习在这个提议中，我们研究了星形胶质细胞中的分子事件（最主要的神经胶质细胞群）影响消退学习中应激诱导的缺陷。更具体地说，我们研究下边缘前额叶皮层星形胶质细胞之间的关系，这是一个对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，压力- 灭绝学习中的诱导缺陷部分是由应激激素作用和增加的发育信号通路，在下边缘前额叶皮层的星形胶质细胞中。为了检验这一假设，我们将研究在操纵应激激素受体功能后，以及下边缘前额叶皮层星形胶质细胞中发育信号级联的活性。我们工作的成功结果将为星形胶质细胞中的分子功能如何有助于压力导致的学习障碍。此外，我们的工作有可能推荐新的细胞类型特异性分子途径，可以有针对性地减轻高度流行和衰弱的创伤后应激障碍的记忆相关方面