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

脑源性神经营养因子在调节心理健康神经炎症中的作用

• 批准号: 10676374
• 负责人: Jason C O'Connor
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676374
• 关键词: Alcohol abuse; Anti-Inflammatory Agents; Association Learning; Astrocytes; Award; Behavior; Brain; Brain-Derived Neurotrophic Factor; Cognitive; Color; Communities; Complex; Coupled; Cues; DNA Methylation; Data; Development; Exposure to; Factor X; Frequencies; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Human; Immune; Impaired cognition; Impairment; Individual; Inflammation; Interleukin-10; Investigation; Knowledge; Kynurenic Acid; Kynurenine; Learning; Lesbian Gay Bisexual Transgender Queer; Mediating; Mental Depression; Mental Health; Mental disorders; Mentors; Metabolic; Metabolic Pathway; Metabolism; Microglia; Mus; Neurobiology; Neuroglia; Parents; Pathogenesis; Pathway interactions; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Predisposing Factor; Prosencephalon; Quality of life; Quinolinic Acid; Reporting; Research; Resistance; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Stress; Suicide; System; Testing; Therapeutically Targetable; Trauma; Veterans; alcohol behavior; behavioral response; brain dysfunction; cognitive function; cognitive process; combat casualty; cytokine; depressive behavior; depressive symptoms; desensitization; epigenetic regulation; experimental study; genetic risk factor; genome-wide; habituation; high risk; military veteran; neural; neuroinflammation; neuroprotection; neurotoxic; novel; psychologic; psychosocial; resilience; response; skills; stressor; suicidal morbidity; suicidal risk; training opportunity; trauma exposure; treatment strategy; virtual

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.

退伍军人继续遭受着更高的抑郁、酗酒和自杀的负担 与一般平民人口相比，这一问题预计会变得更糟。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+社区或有色人种社区中的个人。了解神经生物学的贡献 调节这种增加的风险的底物对于识别高风险个体和发展是必要的。 更好的治疗策略，以治疗遭受痛苦的美国退伍军人。不幸的是，调解机制(S) 脆弱性仍然难以捉摸。我们正在进行的研究发现脑源性神经营养障碍 大脑中的脑源性神经营养因子(BDNF)系统，作为一种遗传风险因子，使人易受心理社会或免疫的影响 压力，以及在父母退伍军人荣誉奖的初始资助期间产生的无数数据，这些数据与 这一补充项目显示，BDNF信号的中断加剧了神经炎症和 炎症诱导的抑郁样行为和认知功能。同时，研究人员还在研究 小胶质细胞上的脑源性神经营养因子系统在很大程度上是父母VA优秀奖的重点，有几个重要的空白 这些知识构成了本补充申请中提出的实验的基础。这个 本补充申请的主要目标是1)支持一个研究密集的指导项目， 加强与其相关的退伍军人奖励的范围和影响，2)提供培训 为Dei导师(Miguel De La Flor)提供了发展其科学技能的机会，同时增加了 退伍军人事务部研究界，最重要的是，3)建立一条新的调查路线，将提供 De la Flor博士准备CDA-2申请并过渡到独立研究职位的基础。更多 具体地说，我们提出了三个具体目标，将在两年内实施，但仍将探索重要 有或无心理或免疫暴露的BDNF功能障碍的未知功能后果 压力。首先，脑源性神经营养因子缺乏作为一个易损性因素的作用，改变了不适应的认知和 将对行为反应进行调查。非联想学习，即习惯化，是一种基本的认知方式 这一过程实际上影响了所有其他高等认知过程，但它往往被忽视。目标1号将探测到这一点 以几种不同的方式进行认知过程。其次，众所周知，神经炎会增加与酒精相关的风险 行为，这是一个特别的问题，对退伍军人产生不利影响，并增加自杀的风险。目标 2将研究脑源性神经营养因子缺乏在酒精相关疾病发展中的作用。 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。 基因可能与心理或免疫压力(创伤)相互作用，造成稳定、持久的失调。

项目成果

Author response to: Modulating kynurenine monooxygenase in microglia: The need for further characterization.

作者回应：调节小胶质细胞中的犬尿氨酸单加氧酶：需要进一步表征。

• DOI: 10.1016/j.psyneuen.2018.08.019
• 发表时间: 2018
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Garrison,AllisonM;Parrott,JenniferM;Tunon,Arnulfo;Delgado,Jennifer;Redus,Laney;O'Connor,JasonC
• 通讯作者: O'Connor,JasonC

GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice.

• DOI: 10.1038/s41598-018-23795-4
• 发表时间: 2018-04-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Chen C;Li X;Ge G;Liu J;Biju KC;Laing SD;Qian Y;Ballard C;He Z;Masliah E;Clark RA;O'Connor JC;Li S
• 通讯作者: Li S

Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain.

• DOI: 10.1016/j.bbi.2017.07.008
• 发表时间: 2017-11
• 期刊: Brain, behavior, and immunity
• 作者: Laumet G;Zhou W;Dantzer R;Edralin JD;Huo X;Budac DP;O'Connor JC;Lee AW;Heijnen CJ;Kavelaars A
• 通讯作者: Kavelaars A

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

• DOI: 10.5498/wjp.v12.i1.77
• 发表时间: 2022-01-19
• 期刊: World journal of psychiatry
• 影响因子: 3.1
• 作者: Porter GA;O'Connor JC
• 通讯作者: O'Connor JC

Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation.

• DOI: 10.1038/tp.2016.200
• 发表时间: 2016-10-18
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Parrott JM;Redus L;Santana-Coelho D;Morales J;Gao X;O'Connor JC
• 通讯作者: O'Connor JC