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: 10676185
• 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/10676185
• 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; Development; Equilibrium; Exhibits; Exposure to; Frequencies; Functional disorder; Funding; Genetic; Genetic Predisposition to Disease; Heterozygote; Hippocampus; 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; Phenotype; 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; Therapeutically Targetable; 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; neural; neurobiological mechanism; neuroinflammation; neuroprotection; neurotoxic; novel therapeutic intervention; pharmacologic; pre-clinical; psychologic; psychosocial; resilience; response; stressor; suicidal; symptomatology; systemic inflammatory response; 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的功能障碍使其易受心理社会压力的影响，并在初始阶段产生大量数据