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

退伍军人继续承受着更高的抑郁、酗酒和自杀负担 比一般平民人口还要多，而且预计问题会变得更严重。事实上，在接下来的10年里， 自杀死亡人数将是战斗伤亡人数的 20 倍以上，前景更加黯淡 LGBTQ 群体或有色人种群体中的个人。了解神经生物学的贡献 介导这种风险增加的基质对于识别风险最高的个体和发展是必要的 更好的治疗策略来治疗遭受痛苦的美国退伍军人。不幸的是，调解这一问题的机制 脆弱性仍然难以捉摸。我们正在进行的研究已经确定了脑源性神经营养功能障碍 大脑中的 BDNF 因子（BDNF）系统作为遗传风险因素，导致心理社会或免疫脆弱性 压力，以及在母公司 VA 优异奖初始资助期间产生的大量数据 该补充项目表明，BDNF 信号传导的破坏会加剧神经炎症， 炎症引起的抑郁样行为和认知功能。虽然研究检验了 小胶质细胞上的 BDNF 系统很大程度上是母公司 VA 优异奖的焦点，有几个重要的差距 保留并构成本补充申请中提出的实验基础的知识。的 此补充申请的主要目标是 1) 支持研究密集型指导项目 增强与其相关的 VA 优异奖的范围和影响力，2) 提供培训 DEI 学员（Miguel de la Flor）有机会发展自己的科学技能，同时增加内部的多样性 VA 研究界，最重要的是，3）建立一个新颖的调查路线，提供 为 de la Flor 博士准备 CDA-2 申请并过渡到独立研究职位奠定了基础。更多 具体来说，我们提出了 3 个具体目标，将在 2 年内实现，这些目标将探讨尚未实现的重要目标 BDNF 功能障碍的未探索的功能后果，无论是否暴露于心理或免疫 压力。首先，BDNF 缺乏作为一种脆弱性因素，可以改变适应不良的认知和认知能力。 将探究行为反应。非联想学习，即习惯化，是一种基本的认知能力 这个过程几乎影响所有其他高级认知过程，但它经常被忽视。目标 1 将对此进行探索 认知过程有几种不同的方式。其次，已知神经炎症会增加与酒精相关的症状 行为，这是一个对退伍军人产生不利影响并增加自杀风险的特殊问题。目标 2 将研究 BDNF 缺乏作为酒精相关疾病发展的加剧因素的作用 行为。最后，将探索小胶质细胞基因表达的表观遗传调控机制 遗传学可能与心理或免疫应激（创伤）相互作用，造成稳定、持久的失调。

Military veterans continue to suffer from a substantially higher burden of depression, alcohol abuse, and suicide than the general civilian population, and the problem is anticipated to get worse. In fact, over the next 10 years, suicide deaths will outnumber combat casualties by more than 20X, and the outlook is even more dire for individuals in the LGBTQ+ community or communities of color. Understanding the contribution of neurobiological substrates that mediate this increased risk is necessary for identifying individuals at highest risk and developing better treatment strategies to treat suffering US veterans. Unfortunately, mechanism(s) mediating this vulnerability remain elusive. Our ongoing research has identified dysfunction of the brain derived neurotrophic factor (BDNF) system in the brain as a genetic risk factor that confers vulnerability to psychosocial or immune stress, and myriad data generated during the initial funding period of the parent VA Merit Award associated with this supplemental project revealed that disruption of BDNF signaling potentiated neuroinflammation and inflammation-induced depressive-like behaviors and cognitive function. While studies examining the role of the BDNF system on microglia are largely the focus of the parent VA Merit Award, there are several important gaps in knowledge that remain and form the basis for the experiments proposed in this supplemental application. The broad objectives of this supplement application are 1) to support a research intensive mentored project that enhances both the scope and impact of the VA Merit Award to which it is associated, 2) to provide a training opportunity for a DEI mentee (Miguel de la Flor) to develop his scientific skillset while increasing diversity within the VA research community, and most importantly, 3) to establish a novel line of investigation that will provide a basis for Dr. de la Flor to prepare a CDA-2 application and transition into an independent research position. More specifically, we propose 3 specific aims that will be carried out over 2 years that will probe important yet unexplored functional consequences of BDNF dysfunction with or without exposure to psychological or immune stress. First, the role of BDNF deficiency as a vulnerability factor that modifies maladaptive cognitive and behavioral responses will be probed. Non-associative learning, namely habituation, is a fundamental cognitive process that impacts virtually all other higher cognitive processes, yet it is often overlooked. Aim 1 will probe this cognitive process in several distinct ways. Next, neuroinflammation is known to increase alcohol-related behaviors, which are a particular problem adversely impacting veterans and increasing the risk for suicide. Aim 2 will investigate the role of BDNF deficiency as an exacerbating factor in the development of alcohol-related behaviors. Finally, epigenetic regulation of microglia gene expression will be explored a mechanism by which genetics may interact with psychological or immune stress (trauma) to create stable, long-lasting dysregulation.