Animal Models of Suicide Relevant Intermediate Behavioral, Neurobiological and M

儿童时期经历的忽视/虐待是未来自杀的主要风险因素 行为可能通过焦虑，抑郁， 和冲动/攻击性。童年逆境、分子/神经生物学之间的机械联系 自杀风险和自杀途径尚未确定。我们建议调查以下方面的关键假设： 1)童年逆境是否是自杀行为、神经生物学和分子的因果前因 表型; 2）逆境诱导对基因表达和表观遗传变异影响的时间过程 在靶基因簇内：3）外周细胞表观遗传标记和 存在于大脑中的那些;以及4）通过“治疗性”干预来探索这种效应的逆转。我们提出 使用小鼠模型，因为小鼠特别适合于机理研究。我们的实验是 旨在平行于中心内的分子和神经生物学人类研究， 通知其他项目。在目标1中，我们将研究是否在小鼠中诱导自杀相关表型。 早期生活逆境与HPA失调，神经生物学变化和基因 大脑中的表达模式应激反应性升高是出现 精神病理学，这一目标将建立HPA功能的母体分离的小鼠，表现出风险 表型（焦虑样、抑郁样、冲动/攻击性）。这一目标也将决定 5-脑中HTT和5-HT 1AR结合作为母体分离/风险表型的函数，并评估 β-肾上腺素能、HPA和神经营养途径内的基因表达，因为这些是生物学上的 与自杀有关的表型在目标2中，我们将确定DNA形式的表观遗传变异的作用， 甲基化作为母体分离诱导效应的潜在分子途径。目标2确定 分离诱导的大脑表观遗传效应是否与血液变化相对应， 这些外周表观遗传变化可用于预测自杀相关风险的后期发展 表型在目标3中，我们将探讨母亲分离诱导的自杀相关影响的可逆性。 表型使用药理学靶向和环境操纵期间的少年 期

The experience of childhood adversity in the form of neglect/abuse is a major risk factor for future suicidal behavior perhaps via long-term changes in molecular and neurobiological substrates of anxiety, depression, and impulsivity/aggression. The mechanistic links between childhood adversity, molecular/neurobiological pathways, and suicide risk have yet to be established. We propose to investigate key hypotheses regarding: 1) whether childhood adversity is a causal antecedent to suicide behavioral, neurobiological, and molecular phenotypes; 2) the time course of adversity-induced effects on gene expression and epigenetic variation within target gene clusters: 3) the degree of concordance between peripheral cell epigenetic marks and those present in the brain; and 4) explore reversal of such effects by "therapeutic" intervention. We propose to use mouse models as mice are especially well suited to mechanistic studies. Our experiments are designed to parallel the molecular and neurobiological human studies within the center and can thus readily inform the other projects. In Aim 1, we will investigate whether suicide-relevant phenotypes in mice induced with eariy life adversity are associated with indices of HPA dysregulation, neurobiological changes, and gene expression patterns in the brain. Heightened stress responsivity is risk factor for the emergence of psychopathology and this aim will establish the HPA function of maternally separated mice that exhibit risk phenotypes (anxiety-like, depressive-like, impulsivity/aggression). This aim will also determine the density of 5-HTT and 5-HT1AR binding in the brain as a function of maternal separation/risk phenotype and assess the expression of genes within serotonergic, HPA, and neurotrophic pathways, as these are biological phenotypes linked to suicide. In Aim 2, we will determine the role of epigenetic variation in the form of DNA methylation as a potential molecular pathway of maternal separation-induced effects. Aim 2 determines whether separation-induced epigenetic effects in the brain correspond to changes in blood and whether these peripheral epigenetic changes can be used to predict the later development of a suicide-relevant risk phenotype. In Aim 3 we will explore the reversibility of maternal-separation induced effects on suicide-relevant phenotypes using pharmacological targeting and environmental manipulations during the juvenile period.