Microglial brain-derived neurotrophic factor (BDNF) in stress and antidepressant responses

项目概要/摘要： 重度抑郁症（MDD）是一种复发性精神疾病，可导致严重残疾， 社会经济负担。目前的MDD治疗需要数周到数月才能有效，许多患者 是治疗抵抗性的，报告症状严重程度没有改善。在这种情况下，研究 旨在了解抑郁症的神经生物学，并确定新的治疗靶点。临床 基础研究表明，内侧前额叶皮质（PFC）功能障碍是脑卒中的主要病理生理学机制， 导致抑郁样行为的特征，包括绝望、社交能力下降和认知能力下降。 损伤特别是，研究表明，抑郁样行为和认知障碍是相关的 内侧PFC内锥体神经元突触数目减少，树突状萎缩。 脑源性神经营养因子（BDNF）是神经可塑性的重要调节因子。确实 BDNF信号缺陷的小鼠具有夸大的应激诱导的神经可塑性缺陷， 与野生型小鼠相比，抑郁样行为。与这项工作相一致，最近的研究表明，BDNF 内侧PFC中的信号传导是氯胺酮或东莨菪碱后快速抗抑郁样作用所必需的。 虽然这些研究暗示BDNF在抑郁症和抗抑郁治疗的神经生物学中， 目前还不清楚是什么细胞类型驱动这种神经营养信号。 精液研究表明，小胶质细胞，大脑中的组织驻留巨噬细胞，积极调节 神经可塑性在生理和病理条件。值得注意的是，最近的研究表明，小胶质细胞特异性 BDNF的缺失减少了运动皮质中谷氨酸受体的表达，这导致了突触功能受损。 对运动学习任务的可塑性。因此，似乎小胶质细胞BDNF是一个关键的调解人， 慢性应激和抗抑郁治疗中的神经可塑性。为了支持这一观点，我们最初的研究表明， 慢性应激降低了PFC中纯化的小胶质细胞中BDNF的表达，这与突触 缺陷和抑郁样行为。进一步的研究表明，氯胺酮给药增加了小胶质细胞， PFC中的BDNF表达与树突棘密度增加和抗抑郁药相关。 比如行为反应为了阐明这些发现，拟议的研究将使用具有小胶质细胞特异性的小鼠。 BDNF耗竭（Cx3cr1CreER：Bdnffl/fl）以测试两个特定目的：1）确定小胶质细胞BDNF缺陷是否赋予 通过增加突触损失和应激后抑郁样行为的应激易感性;和2）检查 小胶质细胞BDNF在快速抗抑郁药的神经生物学反应和行为效应中的作用 氯胺酮或东莨菪碱。本申请中概述的研究意义重大，因为它们将是第一个研究 小胶质细胞BDNF在神经生物学适应中的作用， 行为和抗抑郁治疗。我们希望能发现小胶质细胞的一种新的神经营养作用， 指导MDD和其他神经系统疾病的治疗策略。

Project Summary/Abstract: Major depressive disorder (MDD) is a recurring psychiatric disease that causes significant disability and socioeconomic burdens. Current therapies for MDD take weeks to months to be effective, and many patients are treatment-resistant reporting no improvement in symptom severity. In this context, it is important for research to be aimed at understanding the neurobiology of depression and to identify novel therapeutic targets. Clinical and basic research indicate that dysfunction of the medial prefrontal cortex (PFC) is a primary pathophysiological feature that contributes to depressive-like behaviors, including despair, reduced sociability, and cognitive impairment. In particular, studies show that depressive-like behaviors and cognitive impairments are associated with reduced synapse number and dendritic atrophy of pyramidal neurons in the medial PFC. It is well- established that brain-derived neurotrophic factor (BDNF) is an important regulator of neuroplasticity. Indeed mice deficient in BDNF signaling have exaggerated stress-induced neuroplasticity deficits and worsened depressive-like behaviors compared to wild-type mice. Consistent with this work, recent studies show that BDNF signaling in the medial PFC is required for rapid antidepressant-like effects following ketamine or scopolamine. While these studies implicate BDNF in the neurobiology of depression and antidepressant treatment, it remains unclear what cell type drives this neurotrophic signaling. Seminal work has shown that microglia, the tissue-resident macrophages in the brain, actively regulate neuroplasticity in physiological and pathological conditions. Notably, recent studies show that microglia-specific BDNF depletion reduced glutamate receptor expression in the motor cortex, which led to impaired synaptic plasticity in response to a motor learning task. Thus, it is plausible that microglial BDNF is a critical mediator of neuroplasticity in chronic stress and antidepressant treatment. In support of this idea, our initial studies showed that chronic stress reduced BDNF expression in purified microglia in the PFC, which corresponded with synaptic deficits and depressive-like behavior. Further studies showed that ketamine administration increased microglial BDNF expression in the PFC, which was associated with increased dendritic spine density and antidepressant- like behavioral responses. To expound on these findings proposed studies will use mice with microglia-specific BDNF depletion (Cx3cr1CreER:Bdnffl/fl) to test two specific aims: 1) Determine if deficient microglial BDNF confers stress susceptibility via increased synapse loss and depressive-like behaviors following stress; and 2) Examine the role of microglial BDNF in neurobiological responses and behavioral effects of rapid-acting antidepressants ketamine or scopolamine. Studies outlined in this application are significant because they will be the first to study the role of microglial BDNF in neurobiological adaptations underlying both stress-induced depressive-like behaviors and antidepressant treatment. We expect to identify a novel neurotrophic role for microglia, which may guide treatment strategies for MDD and other neurological conditions.