Animal Models of Suicide: Behavior, Neurobiological and Molecular Phenotypes

自杀动物模型：行为、神经生物学和分子表型

基本信息

批准号：
10408794
负责人：
Rene Hen
金额：
$ 17.5万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408794
关键词：
Adolescent Aggressive behavior Anhedonia Animal Model Autopsy Autoreceptors BDNF gene Behavior Behavioral Behavioral inhibition Blood Brain Brain-Derived Neurotrophic Factor Childhood Chronic DNA Methylation Depression and Suicide Environment Environmental Risk Factor Epigenetic Process Exhibits Exposure to Female Funding Future Gene Expression Gene Expression Profile Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Transcription Genotype Glucocorticoid Receptor Goals Health Hippocampus (Brain)Human Immune Impulsivity Individual Individual Differences Infant Inflammasome Inflammation Inflammatory Link Major Depressive Disorder Measures Mental Depression Mental disorders Molecular Mus NR3C1 gene Neurobiology Neuronal Plasticity Outcome Parents Pathway interactions Peripheral Phenotype Prefrontal Cortex Psychopathology Recording of previous events Risk Risk Factors Rodent Model Role Serotonin Social Interaction Stress Suicide Suicide attempt System Tissue-Specific Gene Expression Transgenic Mice Transgenic Organisms Variant abuse neglect anxiety-like behavior base behavioral outcome behavioral phenotyping bisulfite childhood adversity clinical phenotype cytokine depressive symptoms design early life adversity epigenetic regulation epigenetic variation experience experimental study gene environment interaction genetic manipulation hypothalamic-pituitary-adrenal axis indexing male maternal separation molecular phenotype mouse model neglect neuroinflammation novel postnatal promoter pyrosequencing relating to nervous system resilience response sex suicidal behavior suicidal risk suicide model transcriptome transcriptome sequencing

项目摘要

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.

摘要 – 项目 2 忽视/虐待形式的童年逆境经历是未来自杀的主要风险因素行为可能是通过抑郁症的分子和神经生物学基础的长期变化来实现的冲动/攻击性早年逆境的影响与遗传脆弱性相互作用，从而赋予呼吸。精神病理学风险和不良健康结果之间的机制联系，我们建议，遗传风险、分子/神经生物学途径和自杀风险尚未确定。研究以下关键假设：1) 童年逆境是否与 5-HT1A 基因型相互作用 2）环境风险与遗传风险之间的关系自杀对大脑转录组和表观遗传变异的影响；3）对外周和大脑炎症的影响；环境和遗传脆弱性对自杀行为的综合影响的途径这些炎症体测量与风险行为表型的关系我们建议使用小鼠。小鼠模型特别适合机械研究和转基因操作。实验旨在平行人体研究中的分子、神经生物学和免疫结果在目标 1 中，我们将调查是否有自杀行为。小鼠的相关表型（抑郁样、冲动/攻击性）是通过呼吸的组合早年的逆境（母亲分离）和 5-HT1A 系统的有针对性的基因操纵导致 5-HT1A 自身受体表达升高，随后 5-HT 水平降低，目标 2 决定。早期逆境和大脑中 5-HT1A 自身受体水平升高是否会导致海马体改变和前额皮质转录组（使用 RNA-Seq）以及 BDNF 和 DNA 甲基化的变化 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 Nr3c1 基因的炎症后果。遗传和环境对自杀行为的脆弱性以及这些措施与特定自杀行为的关系为了实现这一目标，我们将分析血液、海马体内的细胞因子水平。和经历过产后母亲分离的小鼠的前额皮质 5-HT1A 自身受体的表达并评估由此产生的大脑内小胶质细胞的激活基因-环境相互作用。