Antecedents of Suicidal Behavior Related Neurobiology

摘要--总体 过去15年，美国自杀人数增加了27%，这要求研究推动预防模式的转变 自杀行为的原因。孔特中心最初4年的资助确定了相关的大脑变化 自杀和非致命性自杀行为，表明共同的原因因素和潜在的预防通过检测 未来的自杀死者。主要发现包括前额叶皮质变薄和齿状回变小，部分原因是 神经元丢失。我们发现HPA轴和炎症体指数存在潜在的原因异常和 营养系统缺乏，包括5-羟色胺系统(更多的5-HT1A自身受体)和低BDNF。 这些发现将遗传学、童年逆境、表观遗传学、情绪调节和认知与正电子发射计算机断层扫描和功能磁共振成像联系起来。 异常、应激反应和自杀行为。目前的提议试图研究神经回路。 以及自杀和非致命性自杀行为中异常应激反应的分子细节，强调 炎症体、HPA轴和脑源性神经营养因子的潜在病因和致病作用。项目1(安德伍德 /Boldri)使用患有严重抑郁障碍(MDD)的自杀者的死后脑组织来检查 儿童期逆境(心理尸检)、神经炎症和前额叶突起/突触团块 大脑皮层、前扣带回皮质和海马区，以及现有的基因组学数据(HPA，营养/凋亡， GABA、Glu、5-HT、BDNF)、神经元和神经胶质细胞数量、生长和凋亡因子、HPA轴和5-羟色胺 系统。项目2(香槟/母鸡)应用母体分离小鼠模型来检查对 同源基因组学、脑生物学与抑郁症、焦虑和攻击行为的关系 过度表达5-HT1a自身受体(GenXenviron)。项目3(Mann)使用PET来量化 抑郁/自杀/攻击/氧化负荷相关的神经递质指数(MAOA)，一种神经炎症 标记(PBR28)，突触标记(UCB-J)和项目4(Ochsner)使用fMRI研究情绪调节 MDD自杀未遂者、MDD非自杀未遂者和健康志愿者的记忆。项目5(赤柱)将 使用生态瞬时评估和TSST生物应激反应(HPA、肾上腺素能和 炎症性)研究与冲动或计划自杀有关的情绪和生物应激反应 行为和报告的童年逆境。项目6(奥格登)将使用高维大脑成像，基因组 和炎症性数据，以开发统计方法来衡量自杀风险。研究结果在以下方面进行了比较 探索性项目旨在测试童年逆境导致更大炎症、受损 5-羟色胺和脑源性神经营养因子的营养作用和与脑改变相关的长期应激反应受损 形态和功能是潜在的自杀风险。

SUMMARY – OVERALL A 27% increase in US suicides in the past 15 years demands a paradigm shift in prevention driven by research into causes of suicidal behavior. The Conte Center’s first 4 years of funding identified related brain changes in suicide and nonfatal suicidal behavior, indicating common causal factors and potential prevention by detecting future suicide decedents. Key findings include thinner prefrontal cortex and smaller dentate gyrus, partly due to neuronal loss. We found potential causal abnormalities in HPA axis and inflammasome indices and deficiencies in trophic systems including the serotonin system (more 5-HT1A autoreceptors) and low BDNF. These findings link genetics, childhood adversity, epigenetics, mood regulation and cognition to PET and fMRI abnormalities, stress responses and suicidal behavior. The current proposal seeks to study the neural circuitry and molecular detail of abnormal stress responses in suicide and nonfatal suicidal behavior, emphasizing potential etiological and pathogenic roles of the inflammasome, HPA axis and BDNF. Project 1 (Underwood /Boldrini) uses postmortem brain tissue from suicides with major depressive disorder (MDD) to examine childhood adversity (psychological autopsy), neuroinflammation and process/synaptic mass in prefrontal cortex, anterior cingulate cortex and hippocampus, and existing data on genomics (HPA, trophic/apoptotoic, GABA, Glu, 5-HT, BDNF), neuron and glial number, growth and apoptotic factors, HPA axis and the serotonin system. Project 2 (Champagne/Hen) applies a maternal separation mouse model to examine effects on homologous genomics, brain biology and depression, anxiety and aggressive behaviors in a mouse model of over-expressing 5-HT1A autoreceptors (geneXenviron). Project 3 (Mann) uses PET to quantify a depression/suicide/aggression/oxidative load-related neurotransmitter index (MAOA), a neuroinflammation marker (PBR28), & a synaptic marker (UCB-J) and Project 4 (Ochsner) uses fMRI to study mood regulation and memory in MDD suicide attempters, MDD nonattempters and healthy volunteers. Project 5 (Stanley) will use ecological momentary assessment and TSST biological stress responses (HPA, adrenergic and inflammatory) to study emotional and biological stress responses with respect to impulsive or planned suicidal behavior and reported childhood adversity. Project 6 (Ogden) will use high dimensional brain imaging, genomic and inflammasome data to develop statistical methods to measure suicidal risk. Findings are compared across projects in exploratory aims to test a model where childhood adversity leads to greater inflammation, impaired serotonin and BDNF trophic effects and long-lasting impaired stress responses related to altered brain morphology and function underlying risk of suicide.!