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：
10207364
负责人：
Rene Hen
金额：
$ 15.75万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207364
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 以忽视/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长期变化的抑郁症分子和神经生物学基质以及冲动/侵略性。早期广告的影响与会议增强的遗传脆弱性相互作用心理病理学和不良健康结果的风险。儿童广告之间的机械联系，遗传风险，分子/神经生物学途径和自杀风险尚未确定。我们建议研究有关的关键假设：1）儿童广告是否与5-HT1A基因型相互作用产生自杀行为的风险增加； 2）环境与遗传风险之间的关系大脑转录组和表观遗传变异的自杀； 3）对周围和脑部炎症的影响环境和遗传脆弱性自杀行为的综合作用的途径和这些炎症小体与风险行为表型的关系。我们建议使用鼠标作为小鼠的模型特别适合机械研究和转基因操作。我们的实验旨在与人类研究中的分子，神经生物学和免疫结局平行在中心内，因此可以轻松地告知其他项目。在AIM 1中，我们将研究自杀是否小鼠的相关表型（抑郁症状，冲动/侵略性）通过结合早期生活广告（孕产妇分离）和对5-HT1A系统的有针对性的遗传操纵在5-HT1A自身受体的表达升高中，随后降低了5-HT水平。 AIM 2确定早期广告和大脑中的5-HT1A自身受体水平是否会导致海马变化和前额叶皮层转录组（使用RNA-SEQ）以及BDNF内的DNA甲基化变化 NR3C1基因（使用Bisulfite pyrosequencing）。在AIM 3中，我们将探讨遗传和环境对自杀行为的脆弱性以及这些措施与特定措施的关系自杀行为表型。为了实现这一目标，我们将介绍血液中的细胞因子水平，海马经历了产后分离的小鼠的前额叶皮层与升高因此，5-HT1A自身受体和评估小胶质细胞激活的表达基因环境相互作用。