Animal Models of Suicide: Behavior, Neurobiological and Molecular Phenotypes

摘要--项目2 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 行为可能通过抑郁症的分子和神经生物学底物的长期变化以及 冲动/好斗。早期生活逆境的影响与遗传易感性相互作用，从而导致更高的遗传脆弱性 精神病理和不良健康后果的风险。童年的逆境， 遗传风险、分子/神经生物学途径和自杀风险尚未确定。我们建议 研究以下关键假设：1)童年逆境是否与5-HT1A基因相互作用 产生自杀行为的高风险；2)环境和遗传风险之间的关系 自杀对脑转录组和表观遗传变异的影响；3)对外周和脑炎症的影响 自杀行为的环境和遗传易感性的综合影响的途径 这些炎症性措施与危险行为表型的关系。我们建议使用鼠标 作为小鼠的模型特别适合于机械学研究和转基因操作。我们的 实验的目的是在人类研究中平行分子、神经生物学和免疫结果。 在中心内，因此可以很容易地通知其他项目。在目标1中，我们将调查自杀是否- 小鼠的相关表型(抑郁样、冲动/攻击性)通过联合 早期生活逆境(母体分离)和对5-HT1A系统进行有针对性的基因操作 5-HT1A自身受体表达升高，随后5-羟色胺水平降低。目标2决定 早期的逆境和大脑中5-HT1A自身受体水平升高是否会导致海马区的改变 和前额叶皮质转录组(使用RNA-Seq)和BDNF内DNA甲基化的变异 NR3C1基因(使用亚硫酸氢盐焦磷酸测序)。在目标3中，我们将探讨 遗传和环境对自杀行为的易感性以及这些措施与特定因素的关系 自杀行为表型。为了实现这一目标，我们将分析血液、海马体中的细胞因子水平 以及出生后母体分离合并升高的小鼠的前额叶皮质 5-HT1a自身受体的表达及其对脑内小胶质细胞激活的影响 基因与环境的相互作用。

SUMMARY – PROJECT 2 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 depression and impulsivity/aggression. The effect of early life adversity interacts with genetic vulnerability to confer heightened risk of psychopathology and adverse health outcomes. The mechanistic links between childhood adversity, genetic risk, molecular/neurobiological pathways, and suicide risk have yet to be established. We propose to investigate key hypotheses regarding: 1) whether childhood adversity interacts with 5-HT1A genotype to generate heightened risk of suicide behavioral; 2) the relationship between environment and genetic risk for suicide on the brain transcriptome and epigenetic variation; 3) the impact on peripheral and brain inflammatory pathways of the combined effects of environmental and genetic vulnerability to suicide behavior and the relationship of these inflammasome measures to risk behavioral phenotypes. We propose to use mouse models as mice are especially well suited to mechanistic studies and transgenic manipulations. Our experiments are designed to parallel the molecular, neurobiological and immune outcomes in 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 (depressive-like, impulsivity/aggression) are heightened through a combination of early life adversity (maternal separation) and a targeted genetic manipulation of the 5-HT1A system that results in elevated expression of 5-HT1A autoreceptors and subsequent decreased 5-HT levels. Aim 2 determines whether early adversity and elevated 5-HT1A autoreceptor levels in the brain result in an altered hippocampal and prefrontal cortex transcriptome (using RNA-Seq) and variation in DNA methylation within the BDNF and Nr3c1 genes (using bisulfite pyrosequencing). In Aim 3 we will explore the inflammatory consequences of genetic and environmental vulnerability to suicide behavior and the relationship of these measures to specific suicide behavior phenotypes. To achieve this aim, we will profile cytokine levels within the blood, hippocampus and prefrontal cortex of mice that have experienced postnatal maternal separation combined with elevated expression of 5-HT1A autoreceptors and assess microglial activation within the brain as a consequence of this gene-environment interaction.