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

项目总结/摘要： 临床和临床前研究已经将突触丢失和受损的前额叶皮层（PFC）功能联系起来， 精神疾病的行为和认知症状，如重度抑郁症（MDD）。 临床前模型，如慢性不可预测的压力（CUS），是研究这些的重要工具。 病理生理机制因为它们概括了关键的神经生物学（即，PFC中的突触丢失）， 行为（即，快感缺乏、工作记忆障碍）方面。这一点很重要，因为 社会心理或环境压力增加了精神疾病发展和复发的风险。 越来越多的证据表明，脑内存在的巨噬细胞，即小胶质细胞，在调节神经元的功能方面具有积极的作用。 神经可塑性在生理和病理条件。为了支持这项工作，我们实验室的研究表明， 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， 慢性压力特别是，CUS增加了中膜神经元集落刺激因子-1（CSF 1）信号传导。 PFC引起小胶质细胞介导的神经元重塑，导致突触缺陷， 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。的 糖皮质激素的作用由糖皮质激素受体（GR）介导，其调节基因转录。 事实上，先前的工作表明，GR信号改变了驱动结构重塑和突触的基因网络。 我们最近的研究表明，GR信号诱导神经元CSF 1 在PFC中的信号传导，并引起PFC中小胶质细胞介导的神经元重塑，这有助于 CUS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（REDD 1;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REDD 1和小胶质细胞TNFα 在调节突触可塑性方面起着关键作用。本申请中的研究将决定 神经元或小胶质细胞GR信号传导和各自的下游介质在病理生理学基础 慢性压力的行为后果。在这里，我们将使用大脑区域和细胞类型特异性遗传和 药理学操作以测试两个特定目的：1）定义神经元GR信号传导的作用， 在应激诱导的CSF 1信号传导、小胶质细胞介导的神经元重塑和相关的 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，因为它们将确定引发压力的分子和细胞适应- 诱导的突触损失的PFC。我们希望产生新的见解细胞类型特异性途径，驱动 压力的神经生物学，这可能会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.