Impact of BDNF expression on neuroimmune activation and depressive-like behaviors

描述（由申请人提供）：慢性病是社会的一个相当大的负担。更糟糕的是，慢性病患者患抑郁症的风险增加。作为慢性疾病的结果而发生的促炎细胞因子被假设为代表这种共病抑郁症的病理机制的主要部分，即使如此，并非每个患有慢性疾病的患者都发展这种特定的共病，并且不知道什么因素导致该患者群体中抑郁症表达的变异性。抑郁症预测的一个潜在生物标志物是脑源性神经营养因子（BDNF）的表达。BDNF不仅被研究为与人类和啮齿动物的抑郁状态的关系，它已被证明与促炎细胞因子相互作用并抑制炎症。此外，神经免疫激活被认为是促炎细胞因子诱导行为变化的机制，也干扰BDNF信号传导。 具体来说，这项建议将测试的假设，BDNF的表达是一个决定性的因素，在神经免疫激活和随后的抑郁样行为的大小后，外周炎症。为了解决这一假设，目标1将建立BDNF缺陷小鼠经历更夸张的抑郁样行为后，外周炎症与更明显的神经免疫激活一致。这将在炎症诱导的抑郁样症状的已建立小鼠模型中完成，然后表征中枢神经免疫应答中的区域特异性变化。特异性目标2将确定在外周炎症期间增加中枢BDNF表达是否可以防止神经免疫激活和抑郁样行为的发展。本提案的最终具体目标将利用离体和体外方法直接阐明改变BDNF表达对小胶质细胞TrkB受体信号传导、小胶质细胞活化和色氨酸沿着犬尿氨酸途径的神经毒性代谢的影响。确定BDNF表达对小胶质细胞活化的影响以及色氨酸和犬尿氨酸代谢的参与不仅将扩展我们对炎症期间共病抑郁症发病机制的理解，而且还可以确定新的诊断或治疗靶点。此外，成功完成所提出的目标将提供第一个数据调查炎症，BDNF表达和抑郁样行为的体内相互作用。 连同纳入总体培训计划的各种学术、培训和充实活动，该建议概述了一个全面的多学科和平衡的框架，以推动受训人员实现成为独立调查员的职业目标。

DESCRIPTION (provided by applicant): Chronic disease represents a considerable burden on society. Worsening this is the increased risk of chronic disease patients to develop a diagnosis of depression. Pro-inflammatory cytokines that occur as a result of chronic disease are hypothesized to represent a major portion of the pathological mechanism of such comorbid depression, Even so, not every patient with a chronic disease develops this specific comorbidity, and it is unknown what factors contribute to the variability of depression expression in this patient population. One potential biomarker for depression predictability is the expression of brain-derived neurotrophic factor (BDNF). Not only has BDNF been studied for its relation to depression status in human and in rodents, it has been shown to interact with pro-inflammatory cytokines and suppress inflammation. Furthermore, neuroimmune activation, which is thought to be the mechanism by which pro-inflammatory cytokines induce behavioral changes, also interferes with BDNF signaling. Specifically, this proposal will test the hypothesis that BDNF expression is a determinative factor in the magnitude of neuroimmune activation and subsequent depressive-like behaviors following peripheral inflammation. To address this hypothesis, Aim 1 will establish that BDNF deficient mice experience more exaggerated depressive-like behaviors following peripheral inflammation concordant with more pronounced neuroimmune activation. This will be accomplished in an established mouse model of inflammation-induced depressive-like symptoms followed by characterization of region specific changes in the central neuroimmune response. Specific Aim 2 will determine if increasing central BDNF expression during peripheral inflammation protects against neuroimmune activation and the development of depressive-like behavior. The final specific aim of this proposal will utilize ex vivo and in vitro approaches to directly elucidate the consequences of altering BDNF expression on microglial TrkB receptor signaling, microglial activation and neurotoxic metabolism of tryptophan along the kynurenine pathway. Defining the impact of BDNF expression on microglia activation and the involvement of the metabolism tryptophan and kynurenine will not only extend our understanding of the pathogenesis of comorbid depression during inflammation, but also it may identify novel diagnostic or therapeutic targets. Further, successful completion of the proposed aims will provide the first data investigating the in vivo interactions of inflammation, BDNF expression, and depressive-like behaviors. Together with a variety of academic, training and enrichment activities that are woven into the overall training plan; this proposal outlines a thorough multidisciplinary and well-balanced framework to advance a trainee towards the career goal of becoming an independent investigator.