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: 10487812
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487812
• 关键词: Adult; Agonist; Alleles; Animals; Anti-Inflammatory Agents; Architecture; Asian; Astrocytes; Attenuated; BDNF gene; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Caucasians; Cells; Chronic; Chronic stress; Corticosterone; Data; Depression and Suicide; Development; Equilibrium; Exhibits; Exposure to; Frequencies; Functional disorder; Funding; Genetic; Genetic Predisposition to Disease; Hippocampus (Brain); Human; Immune; Immune system; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Interleukin-10; Intranasal Administration; Knock-in Mouse; Kynurenic Acid; Kynurenine; Major Depressive Disorder; Mediating; Mental Depression; Mental Health; Mental disorders; Metabolic; Metabolism; Microglia; Modeling; Mus; Mutant Strains Mice; Neurobiology; Neuroglia; Neurons; Pathogenesis; Pathway interactions; Peripheral; Pharmacology; Phenotype; Play; Population; Predisposing Factor; Production; Progress Reports; Prosencephalon; Psychological Stress; Psychosocial Stress; Quinolinic Acid; Regulation; Reporting; Resistance; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Stress; Suicide; Synapses; System; Testing; Transgenic Mice; Tyrosine Phosphorylation; Veterans; Wild Type Mouse; antagonist; behavioral response; brain dysfunction; cytokine; depressive behavior; depressive symptoms; experimental study; frontal lobe; genetic approach; immune activation; innovation; insight; military veteran; mouse model; neurobiological mechanism; neuroinflammation; neurotoxic; novel therapeutic intervention; pre-clinical; psychologic; psychosocial; relating to nervous system; resilience; response; symptomatology; systemic inflammatory response; therapeutic target; treatment strategy

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.

BDNF的功能障碍使人容易受到心理社会压力的影响，在最初的研究中产生了无数的数据。 该项目的资助期显示，BDNF信号传导的中断也会增强神经炎症， 炎症引起的抑郁样行为。众所周知，美国退伍军人的患病率很高， 心理压力和慢性炎症以及不成比例地增加的风险 抑郁和自杀了解神经生物学底物的作用， 风险是必要的，以制定更好的治疗策略，以治疗痛苦的美国退伍军人。不幸的是， 调解这种脆弱性的机制仍然难以捉摸。我们最近的发现表明， BDNF系统代表了抑郁症发展的遗传脆弱性因素，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基质。更 具体地，脑中犬尿氨酸途径的失调与脑缺血的发病机制有关。 抑郁症诊断学具有功能意义的是，犬尿氨酸途径的两个代谢分支是 物理上的隔离。形成犬尿烯酸的神经保护分支存在于星形胶质细胞中。的 形成3-羟基犬尿氨酸和喹啉酸的神经毒性分支存在于小胶质细胞中。大量的 有证据表明犬尿氨酸途径与炎症相关的抑郁症有关。然而，这一角色 压力或炎症诱导的抑郁行为的途径在很大程度上尚未被探索。我们最近 报告说，低水平的压力，包括心理和环境的挑战，增加 神经保护因子犬尿烯酸和抗炎细胞因子IL-10在野生型的前脑，但 而不是BDNF+/-小鼠。与此形成鲜明对比的是，神经毒性犬尿氨酸代谢物3-羟基犬尿氨酸的水平是正常的。 在BDNF+/-小鼠中显著增加。这些观察结果支持了我们的论点， 在野生型小鼠中存在的基因在BDNF缺陷动物中不存在。BDNF基因突变的小鼠 系统表现出明显神经炎症、氧化犬尿氨酸代谢和抑郁样行为 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 在炎症）中，BDNF的活性依赖性释放增加IL-10的产生，这反过来又调节 犬尿氨酸途径代谢导致犬尿烯酸水平增加。在BDNF条件下 缺乏或功能障碍时，这些神经保护机制的缺乏导致应激敏感性 表型我们将使用脑源性神经营养因子杂合小鼠（脑源性神经营养因子+/-小鼠），它们的脑源性神经营养因子显着减少 表达，机械地探索提出的目标。为了验证我们的假设， 模型中，我们将使用携带人bdnf基因的met等位基因的转基因小鼠（BDNFmet敲入小鼠）。这 单核苷酸多态性（rs6265）是与抑郁症和自杀相关的危险因素。的 犬尿氨酸途径可能在大脑对压力的反应中发挥作用是一个创新的观点，这可能 深入了解脆弱性和复原力的调节机制。中概述的临床前实验 这一建议将有助于增加我们对神经生物学机制的理解。 某些个体对抑郁症风险因素的敏感性。拟议的实验还将确定潜在的 新的治疗方法，以减轻抑郁症状和自杀的痛苦退伍军人。