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.

儿童逆境与成年抑郁症（MDD），侵略性特征和更大的风险有关 自杀。这种关系的生物学基础主要是未知的，但有趣的是DNA的发现 在报告儿童逆境中，糖皮质激素受体（GR）基因的甲基化/较少的表达。 压力和自杀还与额叶皮层（PFC）中的细胞较少和树突缩小有关 和海马（HC）。较小的HC量可能构成与压力有关的心理病理学的危险因素。 在MDD自杀中，我们发现较低的5-羟色胺转运蛋白（5-HTT）和较高的5-羟色胺IA受体（5-HTIA） PFC的结合和更高的儿童不良事件率。我们假设这种神经生物学表型 可能是由基因，环境和表观遗传效应引起的。我们旨在确定5-HT1A是否具有结合， 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组的PFC和HC中的神经元和神经元密度或数量相关 年龄和性别匹配的MDD自杀和非精神病患者有和没有报告的儿童逆境 （在15岁之前）和12个非自杀MDD，均具有心理尸检和脑毒理学。我们建议 测量：1）背侧PFC（DPFC）的神经元和神经元密度以及ACC并估计HC的总数； 2）DPFC中的5-HTT和5-HTIA结合以及5-HT1A-免疫反应性（IR）轴突初始初始数量 HC和BDNF-IR神经元密度或BDNF-IR神经元密度或 HC中的DPFC和ACC和BDNF-IR单元格中的数字； 3）确定儿童逆境的影响 在DPFC，ACC和HC中的HPA轴指数上，以及与神经元数或密度的区域相关性； 4）确定 童年逆境对18个候选者的神经元基因表达和甲基化水平的影响 DPFC，ACC和HC中的基因与AIM 1相同的5组中。 探索目的将：1）将MDD与自杀或逆境的影响分开 BDNF-IR细胞密度，在DPFC和ACC中，或在HC中进行比较，比较自杀和非自杀MDD 群体； 2）测试终生侵略分数与儿童逆境，神经元和神经胶质的关系 数量或密度，5-羟色胺指数，HPA轴指数，基因表达和甲基化。