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

描述(申请人提供)：慢性病给社会带来了相当大的负担。更糟糕的是，慢性病患者被诊断为抑郁症的风险增加。由于慢性疾病而产生的促炎细胞因子被认为代表了这种并存抑郁的主要病理机制，即使如此，并不是每个慢性病患者都会发生这种特定的并存疾病，目前还不清楚是什么因素导致了这种患者群体中抑郁表达的变异性。脑源性神经营养因子(BDNF)的表达是抑郁症可预测性的一个潜在生物标志物。BDNF不仅因其与人类和啮齿动物抑郁状态的关系而被研究，而且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改变的机制，也干扰了BDNF信号转导。具体地说，这项提议将检验这样一个假设，即BDNF的表达是外周炎症后神经免疫激活和随后的抑郁样行为的大小的决定因素。为了解决这一假设，目标1将确立BDNF缺陷小鼠在外周炎症后经历更夸张的抑郁样行为，这与更明显的神经免疫激活相一致。这将在已建立的炎症诱导的抑郁样症状的小鼠模型中完成，随后描述中枢神经免疫反应的区域特异性变化。具体目标2将确定在外周炎症过程中增加中枢BDNF表达是否可以防止神经免疫激活和抑郁样行为的发展。该提案的最后一个具体目标将利用体外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、小胶质细胞激活和色氨酸沿着犬尿氨酸途径的神经毒性代谢的影响。明确BDNF的表达对小胶质细胞激活的影响以及代谢色氨酸和犬尿氨酸的参与，不仅将扩大我们对炎症过程中并发抑郁的发病机制的理解，还可能找到新的诊断或治疗靶点。此外，成功完成拟议的AIMS将提供第一个数据，研究炎症、BDNF表达和抑郁样行为在体内的相互作用。以及各种学术、培训和丰富活动，这些活动被编入整个培训计划；这项提议勾勒出一个彻底的多学科和平衡的框架，以推动受训人员朝着成为独立调查员的职业目标迈进。

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.