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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