Antecedents of Suicidal Behavior Related Neurobiology

描述(由申请者提供)：美国每年有3万多人自杀，自杀未遂人数是美国的十倍。不幸的是，死亡率和发病率在过去20年中保持稳定，这表明需要转变预防模式。这种转变取决于提高我们对自杀行为原因的认识。孔特中心将采用多学科方法来研究报告的童年逆境如何塑造自杀行为的素质。项目1(Arango)将使用患有严重抑郁障碍(MDD)的自杀者的死后脑组织来研究童年逆境(心理尸检)与来自前额叶皮质、前扣带回皮质和海马神经元的候选基因表达的关系，以及生长和凋亡因子、HPA轴指数和神经元、神经胶质细胞数量和5-羟色胺系统的靶点。自杀和攻击性特征的相关性将被确定。项目2(香槟)将使用母体剥夺小鼠模型来检查对DNA甲基化和相同基因表达的影响，以及对相同大脑生物学和抑郁、焦虑和攻击行为的影响。项目3(Mann)和项目4(Ochsner)将研究同一组MDD自杀未遂者、MDD非未遂者和健康志愿者，并量化脑神经递质指数和Fmr反应，以评估对情绪的认知控制，每个指标都与严重抑郁和自杀行为有关。他们将评估已识别的回路变化与报告的童年逆境的关系。项目5(Stanley)将对P3和P4中的所有受试者进行临床表征，然后确定报告的童年逆境与攻击特征(反应性和主动性攻击)的关系，然后将攻击类型与应激反应和自杀行为类型联系起来。攻击性和应激反应将通过实验室测试和现实世界中的生态瞬时评估来衡量。P5和P3的结果在探索性目标(5-羟色胺功能受损和更强的攻击性)和P4(反应性个人和对情绪的较弱认知控制)方面进行了比较。项目6(Ogden)将使用高维大脑成像数据来开发一种新的方法来衡量自杀行为的风险。然后，该方法可以应用于遗传和其他高维数据集。这些项目将有助于阐明早期不良经历如何影响基因表达和脑生物学，从而增加以后生活中自杀行为的风险。

DESCRIPTION (provided by applicant): Annually, the US has 30,000+ suicides and ten times as many suicide attempts. Unfortunately, mortality and morbidity have remained steady over the last two decades, suggesting that a paradigm shift in prevention is required. Such a shift hinges on improving our knowledge regarding the causes of suicidal behavior. The Conte Center will employ a multidisciplinary approach to study how reported childhood adversity can mold the diathesis for suicidal behavior. Project 1 (Arango) will use postmortem brain tissue from suicides with major depressive disorder (MDD) to examine the relationship of childhood adversity (psychological autopsy) to candidate gene expression in neurons from prefrontal cortex, anterior cingulate cortex and hippocampus, as well as growth and apoptotic factors, HPA axis indices and targets in terms of neuron and glial number and the serotonin system. Correlations with suicide and aggressive traits will be determined. Project 2 (Champagne) will use a maternal deprivation mouse model to examine effects on DNA methylation and expression of the same genes, and effects on the same brain biology and depression, anxiety and aggressive behaviors. Project 3 (Mann) and Project 4 (Ochsner) will study the same set of MDD suicide attempters, MDD nonattempters and healthy volunteers and quantify brain neurotransmitter indices and fMR responses to evaluate cognitive control of emotion, each relevant to major depression and suicidal behavior. They will evaluate the relationship of identified circuitry changes to reported childhood adversity. Project 5 (Stanley) will clinically characterize all the subjects in P3 and P4 and then determine the relationship of reported childhood adversity to aggressive traits (reactive and proactive aggression) and then relate aggression type to stress responsiveness and type of suicidal behavior. Aggression and stress responses will be measured by lab tests and by ecological momentary assessment in the real world. Findings in P5 and P3 are compared in exploratory aims (impaired serotonin function and greater aggression) and P4 (reactive individuals and weaker cognitive control over mood). Project 6 (Ogden) will use high dimensional brain imaging data to develop a novel method to measure risk for suicidal behavior. This method can then be applied to genetic and other high dimensional data sets. These projects will help elucidate how early adverse experiences affect gene expression and brain biology to increase risk of suicidal behavior later in life.