Neurobiology of Suicide: Childhood Adversity and Epigenetics

儿童时期的逆境与成年后抑郁(MDD)、攻击性特征和 自杀。这种关系的生物学基础大多是未知的，除非有有趣的DNA发现 报告童年逆境的自杀者糖皮质激素受体(GR)基因甲基化/表达降低。 压力和自杀也与前额叶皮质(PFC)的细胞减少和树突萎缩有关。 和海马区(HC)。较小的HC体积可能构成与应激相关的精神病理的危险因素。 在MDD自杀患者中，我们发现较低的5-HTT和较高的5-HTIA受体(5-HTIA) PFC绑定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造成的。我们的目标是确定5-HT1A结合， 脑源性神经营养因子、下丘脑-垂体-肾上腺皮质(HPA)轴的测量和候选基因的表达 和甲基化水平与PFC和HC的神经元和神经胶质细胞密度或数量相关。 年龄和性别匹配的MDD自杀者和有或没有报告童年逆境的非精神控制组 (15岁以前)和12例非自杀性MDDS，均进行了心理尸检和脑毒学检查。我们建议 测量：1)背侧前额叶(DPFC)和前交叉韧带(ACC)的神经元和神经胶质细胞密度，并估计HC的总数； 2)DPFC和ACC内5-HTT和5-HTIA的结合及5-HT1A免疫反应阳性轴突的数目 大鼠齿状回颗粒细胞层的节段与脑源性神经营养因子免疫反应神经元密度 DPFC和ACC的数量和HC的BDNF-IR细胞数量；3)决定儿童逆境的影响 DPFC、ACC和HC的HPA轴指数及其与神经元数量或密度的区域相关性；4)确定 童年逆境对18名应征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DPFC、ACC和HC中的基因。 探索性目标将：1)将MDD与自杀或逆境对神经元、神经胶质细胞和 DPFC和ACC的BDNF-IR细胞密度，或HC中的数量，比较自杀和非自杀的MDD 终生攻击性得分与童年逆境、神经元和神经胶质细胞的关系 数量或密度、5-羟色胺指数、HPA轴指数、基因表达和甲基化。

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.