Animal Models of Suicide Relevant Intermediate Behavioral, Neurobiological and M

以忽视/虐待的形式经历的童年逆境是未来自杀的主要危险因素 行为可能是通过焦虑、抑郁、 以及冲动/好斗。童年逆境、分子/神经生物学之间的机制联系 自杀途径和自杀风险尚未确定。我们建议调查有关以下方面的关键假设： 1)童年逆境是否是自杀行为、神经生物学和分子方面的因果先行因素 表型；2)逆境诱导基因表达和表观遗传变异的时间进程 在靶基因簇内：3)外周细胞表观遗传标记与 这些存在于大脑中；以及4)探索通过“治疗性”干预来逆转这种影响。我们建议 使用小鼠模型作为小鼠特别适合于机械学研究。我们的实验是 旨在与该中心内的分子和神经生物学人体研究平行进行，因此可以很容易地 通知其他项目。在目标1中，我们将调查与自杀相关的表型是否诱导了小鼠 早期生活逆境与HPA失调指标、神经生物学变化和基因有关 大脑中的表达模式。应激反应增强是出现 这一目标将建立母系分离的小鼠的HPA功能，这些小鼠表现出风险 表型(焦虑、抑郁、冲动/攻击性)。这一目标还将决定 5-HTT和5-HT1AR在大脑中的结合作为母体分离/风险表型的函数并评估 5-羟色胺能、HPA和神经营养通路中的基因表达，因为这些都是生物学的 表型与自杀有关。在目标2中，我们将确定dna形式的表观遗传变异的作用。 甲基化是母体分离效应的潜在分子途径。目标2决定 分离引起的脑内表观遗传效应是否对应于血液的变化，以及 这些外周表观遗传变化可以用来预测自杀相关风险的以后发展。 表型。在目标3中，我们将探索母系分离对自杀相关影响的可逆性。 利用药物靶向和环境控制在青少年时期的表型 句号。

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.