Neurobiology of Suicide: Childhood Adversity and Epigenetics

自杀的神经生物学：童年逆境和表观遗传学

• 批准号: 8917362
• 负责人: Victoria Arango
• 金额: --
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917362
• 关键词: Adult; Adverse event; Aggressive behavior; Animals; Anterior; Anxiety Disorders; Apoptosis; Apoptotic; Autopsy; Binding; Biological; Brain; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cell Count; Cell Density; Childhood; Complex; DNA Methylation; Dendritic Cells; Disease susceptibility; Dorsal; Environment; Environmental Risk Factor; Epigenetic Process; Gene Expression; Genes; Genetic; Glucocorticoid Receptor; Hippocampus (Brain); Homeostasis; Hypothalamic structure; Instruction; Life Stress; Major Depressive Disorder; Measures; Mental Depression; Methylation; Neurobiology; Neuroglia; Neurons; Parahippocampal Gyrus; Phenotype; Pituitary Gland; Prefrontal Cortex; Prevention; Psychopathology; Receptor Gene; Reporting; Risk; Risk Factors; Role; Serotonin; Stress; Suicide; Testing; Toxicology; age group; base; biological adaptation to stress; cell growth; cingulate cortex; density; dentate gyrus; granule cell; indexing; interest; psychologic; receptor; receptor binding; serotonin transporter; sex; social; suicidal behavior; trait

Childhood adversity is associated with greater risk for adulthood depression (MDD), aggressive traits and suicide. The biological basis of this relationship is mostly unknown but for the interesting finding of DNA methylation/less expression of the glucocorticoid receptor (GR) gene in suicides reporting childhood adversity. Stress and suicide are also associated with fewer cells and dendritic shrinkage in prefrontal cortex (PFC) and hippocampus (HC). Smaller HC volume may constitute a risk factor for stress-related psychopathology. In MDD suicides we find lower serotonin transporter (5-HTT) and higher serotonin IA receptor (5-HTIA) binding in PFC and higher rate of childhood adverse events. We hypothesize that this neurobiological phenotype may result from genes, environment and epigenetic effects. We aim to determine whether 5-HT1A binding, BDNF, measures of the hypothalamus-pituitary-adrenocortical (HPA) axis and candidate gene expression and methylation levels, correlate with neuron and glia density or number in PFC and HC in 5 groups of age- and sex-matched MDD suicides and nonpsychiatric controls with and without reported childhood adversity (before 15y) and 12 non suicide MDDs, all with psychological autopsy and brain toxicology. We propose to measure: 1) neuronal and glial density in dorsal PFC (dPFC) and ACC and estimate total number in HC; 2) 5-HTT and 5-HTIA binding in dPFC and ACC and number of 5-HT1A-immunoreactive (IR) Axonal Initial Segments in the granule cell layer of the dentate gyrus (DG) of the HC and BDNF-IR neuron density or number in dPFC and ACC and BDNF-IR cell number in HC; 3) Determine the effect of childhood adversity on HPA axis indices in dPFC, ACC and HC, and regional correlations with neuron number or density; 4) Determine the effect of childhood adversity on neuronal gene expression and methylation levels of 18 candidate genes in dPFC, ACC and HC in the same 5 groups as Aim 1. Exploratory aims will: 1) separate the effect of MDD from that of suicide or adversity on neuron, glia and BDNF-IR cell density, in dPFC and ACC, or number, in HC, comparing the suicide and non-suicide MDD groups; 2) test the relationship between lifetime aggression scores and childhood adversity, neuron and glia number or density, serotonin indices, HPA axis indices, gene expression and methylation.

童年逆境与成年抑郁症（MDD）、攻击性特征和 自杀。这种关系的生物学基础大多未知，但 DNA 的有趣发现 报告童年逆境的自杀者中糖皮质激素受体（GR）基因的甲基化/表达减少。 压力和自杀也与前额皮质 (PFC) 细胞减少和树突萎缩有关 和海马体（HC）。较小的 HC 体积可能构成与压力相关的精神病理学的危险因素。 在 MDD 自杀中，我们发现血清素转运蛋白 (5-HTT) 较低，而血清素 IA 受体 (5-HTIA) 较高 PFC 的结合和较高的儿童不良事件发生率。我们假设这种神经生物学表型 可能是基因、环境和表观遗传效应的结果。我们的目的是确定 5-HT1A 是否结合， BDNF、下丘脑-垂体-肾上腺皮质 (HPA) 轴和候选基因表达的测量 和甲基化水平，与 5 组 PFC 和 HC 中的神经元和胶质细胞密度或数量相关 年龄和性别匹配的 MDD 自杀率和非精神科对照（有或没有报告童年逆境） （15 岁之前）和 12 个非自杀性 MDD，全部进行了心理尸检和脑毒理学。我们建议 测量：1) 背侧 PFC (dPFC) 和 ACC 中的神经元和胶质细胞密度，并估计 HC 中的总数； 2) dPFC 和 ACC 中的 5-HTT 和 5-HTIA 结合以及 5-HT1A 免疫反应性 (IR) 轴突初始数量 HC 和 BDNF-IR 神经元密度的齿状回 (DG) 颗粒细胞层中的片段或 dPFC 和 ACC 中的细胞数以及 HC 中的 BDNF-IR 细胞数； 3）确定童年逆境的影响 dPFC、ACC 和 HC 中的 HPA 轴指数，以及与神经元数量或密度的区域相关性； 4）确定 童年逆境对 18 名候选者神经元基因表达和甲基化水平的影响 与目标 1 相同的 5 组中的 dPFC、ACC 和 HC 基因。 探索性目标将：1）将抑郁症的影响与自杀或逆境对神经元、神经胶质细胞和神经元的影响区分开来。 BDNF-IR 细胞密度（以 dPFC 和 ACC 为单位）或数量（以 HC 为单位），比较自杀和非自杀 MDD 团体； 2）测试终生攻击性得分与童年逆境、神经元和神经胶质细胞之间的关系 数量或密度、血清素指数、HPA 轴指数、基因表达和甲基化。