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

项目摘要/摘要： 临床和临床前研究已将突触丢失和前额叶皮质(PFC)功能受损与 精神疾病的行为和认知症状，如严重抑郁症(MDD)。 临床前模型，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，概括了关键的神经生物学(即，PFC中的突触丢失)和 MDD的行为方面(即快感缺失、工作记忆障碍)。这一点意义重大，因为暴露于 心理社会或环境应激源会增加发展和精神疾病复发的风险。 越来越多的证据表明，驻留在脑内的巨噬细胞，小胶质细胞，在调节中起着积极的作用。 生理和病理条件下的神经可塑性。为了支持这项工作，我们实验室的研究表明 神经元-小胶质细胞的动态相互作用有助于下列神经生物学和行为后果 慢性压力。特别是，CUS增加了内侧脑区神经细胞集落刺激因子-1(CSF1)的信号。 PFC，它刺激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。 应激诱导的糖皮质激素释放与精神疾病的病理生理学有关。这个 糖皮质激素的作用是由糖皮质激素受体(GR)介导的，GR调节基因转录。 事实上，先前的工作表明，GR信号改变了驱动结构重构和突触的基因网络 前额叶锥体神经元的丢失。我们最近的研究表明，GR信号诱导神经元CSF1 PFC中的信号并刺激小胶质细胞介导的PFC中的神经元重塑，这有助于 CUS术后抑郁行为的发展。这项工作还揭示了GR信号调节特定的 神经元(Redd1；发育调控和DNA损伤反应1)和小胶质细胞的分子通路 (肿瘤坏死因子α；肿瘤坏死因子α)。这些发现是相关的，因为神经元Redd1和小胶质细胞肿瘤坏死因子α 在调节突触可塑性方面起着关键作用。本应用程序中的研究将确定 神经元或小胶质细胞GR信号及其下游介体在相关病理生理学中的作用 慢性压力的行为后果。在这里，我们将使用特定于大脑区域和细胞类型的基因和 药理学操作以测试两个特定的目的：1)确定神经元GR信号和 应激诱导的CSF1信号通路中的下游Redd1、小胶质细胞介导的神经元重塑及其相关 2)研究小胶质细胞GR信号和下游肿瘤坏死因子α在应激中的作用。 诱导的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-- 在前额叶诱发突触丢失。我们希望对驱动细胞类型的特定路径产生新的见解 应激的神经生物学，这可能指导精神疾病的治疗策略。

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.