Defining neuron- and microglia-specific contributions to prefrontal cortex dysfunction in chronic stress

定义神经元和小胶质细胞对慢性应激中前额皮质功能障碍的特异性贡献

基本信息

批准号：
10159981
负责人：
Eric S Wohleb
金额：
$ 39.14万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2020-05-06 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10159981
关键词：
Anhedonia Attenuated Behavior Behavior assessment Behavioral Behavioral Symptoms Brain Brain region Chronic Chronic stress Clinical Research Cognitive Cytomegalovirus DNA Damage Development Electrophysiology (science)Exposure to Functional disorder Gene Expression Profiling Genes Genetic Genetic Transcription Glucocorticoid Receptor Glucocorticoids Glutamate Receptor Impaired cognition Impairment Infusion procedures Link Macrophage Colony-Stimulating Factor Major Depressive Disorder Medial Mediating Mediator of activation protein Memory impairment Mental disorders Microglia Molecular Mus Neurobehavioral Manifestations Neurobiology Neuronal Plasticity Neurons Pathologic Pathway interactions Pharmacology Physiological Pre-Clinical Model Prefrontal Cortex Proteins Receptor Signaling Recombinants Recurrence Regulation Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Self Care Short-Term Memory Signal Transduction Slice Stress Structure Synapses Synaptic plasticity Synaptosomes TNF gene Testing Viral Work behavioral impairment calmodulin-dependent protein kinase II cell type depressive behavior depressive symptoms environmental stressor glucocorticoid-induced orphan receptor hippocampal pyramidal neuron insight knock-down macrophage novel overexpression preclinical study prevent psychosocial stressors response tool trafficking transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY/ ABSTRACT: Clinical and preclinical studies have linked synapse loss and impaired prefrontal cortex (PFC) function to behavioral and cognitive symptoms of psychiatric diseases, such as major depressive disorder (MDD). Preclinical models, such as chronic unpredictable stress (CUS), are important tools to study these pathophysiological mechanisms as they recapitulate key neurobiological (i.e., synapse loss in PFC) and behavioral (i.e., anhedonia, working memory impairment) aspects of MDD. This is significant because exposure to psychosocial or environmental stressors increases risk of development and recurrence of psychiatric disease. Accumulating evidence shows that the brain-resident macrophages, microglia, have an active role in regulating neuroplasticity in physiological and pathological conditions. In support of this work, research in our lab indicates that dynamic neuron-microglia interactions contribute to neurobiological and behavioral consequences following chronic stress. In particular, CUS increases neuronal colony stimulating factor-1 (CSF1) signaling in the medial PFC, which provokes microglia-mediated neuronal remodeling that contributes to synaptic deficits and behavioral and cognitive consequences. Stress-induced release of glucocorticoids are implicated in the pathophysiology of psychiatric diseases. The actions of glucocorticoids are mediated by glucocorticoid receptors (GR), which regulate gene transcription. Indeed prior work shows that GR signaling alters gene networks that drive structural remodeling and synapse loss on pyramidal neurons in the PFC. Our recent studies indicate that GR signaling induces neuronal CSF1 signaling in the PFC and provokes microglia-mediated neuronal remodeling in the PFC, which contributes to development of depressive behaviors after CUS. This work also revealed that GR signaling regulates specific molecular pathways in neurons (REDD1; regulated in development and DNA damage response 1) and microglia (TNFα; tumor necrosis factor-α). These findings are relevant because both neuronal REDD1 and microglial TNFα have critical roles in regulating synaptic plasticity. Studies in this application will determine the contributions of neuronal or microglial GR signaling and respective downstream mediators in the pathophysiology underlying behavioral consequences of chronic stress. Here we will use brain region- and cell type-specific genetic and pharmacological manipulations to test two specific aims: 1) Define the role of neuronal GR signaling and downstream REDD1 in stress-induced CSF1 signaling, microglia-mediated neuronal remodeling, and associated behavioral consequences; and 2) Examine the role of microglial GR signaling and downstream TNFα in stress- induced microglia-mediated neuronal remodeling, synaptic deficits, and associated behavioral consequences. These studies are significant because they will identify molecular and cellular adaptations that initiate stress- induced synapse loss in the PFC. We expect to generate novel insight into cell type-specific pathways that drive the neurobiology of stress, which may guide treatment strategies for psychiatric disease.

项目摘要/摘要：临床和临床前研究已将突触丧失和前额皮质 (PFC) 功能受损与精神疾病的行为和认知症状，例如重度抑郁症（MDD）。临床前模型，例如慢性不可预测应激（CUS），是研究这些问题的重要工具病理生理机制，因为它们概括了关键的神经生物学（即 PFC 中的突触损失）和 MDD 的行为（即快感缺乏、工作记忆障碍）方面这一点很重要，因为暴露。社会或环境压力会增加精神疾病发生和复发的风险。越来越多的证据表明，大脑中的巨噬细胞、小胶质细胞在调节为了支持这项工作，我们实验室的研究表明生理和病理条件下的神经可塑性。动态神经元-小胶质细胞相互作用有助于神经生物学和行为后果特别是慢性压力，CUS 会增加内侧神经元集落刺激因子 1 (CSF1) 信号传导。 PFC，它会引发小胶质细胞介导的神经元重塑，从而导致突触缺陷和行为和认知后果。压力诱导的糖皮质激素释放与精神疾病的病理生理学有关。糖皮质激素的作用是由糖皮质激素受体（GR）介导的，它调节基因转录。事实上，之前的研究表明 GR 信号传导改变了驱动结构重塑和突触的基因网络我们最近的研究表明，GR 信号传导会诱导神经元 CSF1。 PFC 中的信号传导并引发 PFC 中小胶质细胞介导的神经元重塑，这有助于这项工作还揭示了 GR 信号调节特定的功能。神经元（REDD1；在发育和 DNA 损伤反应中受调节 1）和小胶质细胞中的分子通路（TNFα；肿瘤坏死因子-α）。这些发现是相关的，因为神经元 REDD1 和小胶质细胞 TNFα 均存在相关性。在调节突触可塑性方面具有关键作用。该应用中的研究将确定其贡献。神经或小胶质细胞 GR 信号传导及其病理生理学中各自的下游介质在这里，我们将使用大脑区域和细胞类型特异性的遗传和慢性压力的行为后果。药理学操作来测试两个特定目标：1）定义神经元 GR 信号传导的作用和 REDD1 下游应激诱导的 CSF1 信号转导、小胶质细胞介导的神经元重塑以及相关行为后果；2) 检查小胶质细胞 GR 信号传导和下游 TNFα 在应激中的作用诱导小胶质细胞介导的神经元重塑、突触缺陷和相关的行为后果。这些研究意义重大，因为它们将识别引发压力的分子和细胞适应我们希望对驱动 PFC 的细胞类型特异性途径产生新的见解。压力的神经生物学，可以指导精神疾病的治疗策略。