Role of Brain-Derived Neurotrophic Factor in Regulating Neuroinflammation in Mental Health

脑源性神经营养因子的功能障碍使其容易受到心理社会压力的影响，并且在最初的 该项目的资助期显示，BDNF信号的中断也加剧了神经炎症和 炎症诱导的抑郁样行为。众所周知，美国退伍军人患上了高发病率的 心理压力和慢性炎症状况以及不成比例的增加的风险 抑郁和自杀。对调节这一过程的神经生物学底物的贡献的理解增加了 对于制定更好的治疗策略来治疗遭受痛苦的美国退伍军人来说，风险是必要的。不幸的是， 调解这一漏洞的机制(S)仍然难以捉摸。我们最近的发现表明，大脑的功能障碍 BDNF系统代表了抑郁症发生的遗传易感性因素，初步数据 已经确定了似乎介导这种脆弱性的治疗靶向神经底物。更多 具体地说，脑组织中犬尿氨酸途径的失调与脑白质瘤的发病机制有关。 抑郁症状学。具有功能意义的犬尿氨酸途径的两个代谢分支是 身体上被隔开了。形成犬尿酸的神经保护分支驻留在星形胶质细胞中。这个 神经毒性分支存在于小胶质细胞中，形成3-羟基犬尿氨酸和喹啉酸。一大堆 有证据表明犬尿氨酸途径与炎症相关的抑郁症有关。然而，这其中的一个角色 应激或炎症诱导的抑郁行为的途径在很大程度上还没有被探索。我们最近做了 报告称，由心理社会和环境挑战组成的低水平压力会增加 野生型前脑中的神经保护因子犬尿酸和抗炎细胞因子IL-10，但 而不是BDNF+/-小鼠。与之形成鲜明对比的是，神经毒性犬尿氨酸代谢物3-羟基犬尿氨酸的水平 在BDNF+/-小鼠中显著升高。这些观察结果支持了我们的观点，即保护机制 在野生型小鼠中不存在，在BDNF缺乏的动物中不存在。脑源性神经营养因子基因突变小鼠 系统表现出明显的神经炎症、犬尿氨酸氧化代谢和抑郁样行为 相对于野生型小鼠。我们的总体假设是，在暴露于抑郁风险因素(压力或 炎症)，BDNF的活性依赖性释放增加IL-10的产生，进而调节 犬尿氨酸途径代谢导致犬尿酸水平升高。在BDNF条件下 缺乏或功能障碍，这些神经保护机制的缺失导致应激敏感 表型。我们将使用BDNF杂合子小鼠(BDNF+/-小鼠)，这些小鼠表现出BDNF显著减少 表达，机械地探索提出的目标。在与翻译相关的文本中测试我们的假设 模型，我们将使用携带人BDNF基因MET等位基因的转基因小鼠(BDNFmet敲入小鼠)。这 单核苷酸多态(Rs6265)是抑郁症和自杀的危险因素。那就是 犬尿氨酸通路可能在大脑对压力的反应中发挥作用是一个创新的视角，它可能 洞察(S)调节脆弱性和韧性的机制。中概述的临床前实验 这项建议将有助于增加我们对潜在的神经生物学机制的理解 某些个体对抑郁风险因素的敏感性。拟议中的实验还将识别潜在的 减轻退伍军人抑郁症状和自杀倾向的新治疗方法。

Dysfunction in BDNF confers vulnerability to psychosocial stress, and myriad data generated during the initial funding period of this project revealed that disruption of BDNF signaling also potentiated neuroinflammation and inflammation-induced depressive-like behaviors. The US veteran population is well known to suffer high rates of psychological stress and chronic inflammatory conditions as well as disproportionately increased risk of depression and suicide. Understanding the contribution of neurobiological substrates that mediate this increased risk is necessary for developing better treatment strategies to treat suffering US veterans. Unfortunately, mechanism(s) mediating this vulnerability remain elusive. Our recent discoveries suggest that dysfunction in the BDNF system represents a genetic vulnerability factor for the development of depression, and preliminary data have identified therapeutically targetable neural substrates that appear to mediate this vulnerability. More specifically, dysregulation of the kynurenine pathway in the brain has been implicated in the pathogenesis of depressive symptomotology. Of functional significance, two metabolic branches of the kynurenine pathway are physically compartmentalized. The neuroprotective branch that forms kynurenic acid resides in astrocytes. The neurotoxic branch that forms 3- hydroxykynurenine and quinolinic acid resides in microglia. A large body of evidence implicates the kynurenine pathway in depression associated with inflammation. However, a role for this pathway in stress- or inflammation-induced depressive behavior has been largely unexplored. We have recently reported that low-level stress, consisting of psychosocial and environmental challenges, increases neuroprotective factors kynurenic acid and the anti-inflammatory cytokine IL-10 in the forebrain of wild-type, but not BDNF+/- mice. In striking contrast, levels of the neurotoxic kynurenine metabolite 3-hydroxykynurenine are markedly increased in BDNF+/- mice. These observations support our contention that protective mechanisms present in wild-type mice are absent in BDNF deficient animals. Mice with genetic disruptions in the BDNF system exhibit pronounced neuroinflammation, oxidative kynurenine metabolism and depressive-like behavior relative to wild-type mice. Our overall hypothesis is that during exposure to depression risk factors (stress or inflammation), the activity-dependent release of BDNF increases IL-10 production, which in turn modulates kynurenine pathway metabolism resulting in increased levels of kynurenic acid. Under conditions of BDNF deficiency or dysfunction, the absence of these neuroprotective mechanisms results in a stress-sensitive phenotype. We will use BDNF heterozygous mice (BDNF+/- mice), which exhibit marked reductions in BDNF expression, to mechanistically explore the aims proposed. To test our hypotheses in a translationally relevant model, we will use transgenic mice carrying the met allele of the human bdnf gene (BDNFmet knock-in mice). This single nucleotide polymorphism (rs6265) is a risk factor associated with depression and suicide. That the kynurenine pathway may play a role in the brain's response to stress is an innovative perspective, which may provide insight into mechanism(s) mediating vulnerability and resilience. The preclinical experiments outlined in this proposal will serve to increase our understanding of the neurobiological mechanisms underlying the sensitivity of certain individuals to depression risk factors. The proposed experiments will also identify potentially novel therapeutic approaches to mitigate depression symptoms and suicidality in suffering veterans.