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Animal Models of Suicide Relevant Intermediate Behavioral, Neurobiological and M

自杀相关中级行为、神经生物学和 M 的动物模型

基本信息

批准号：
8605254
负责人：
FRANCES A. CHAMPAGNE
金额：
$ 18.3万
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605254
关键词：
Adolescent Adrenal Glands Aggressive behavior Amygdaloid structure Animal Model Anxiety Autopsy Behavioral Binding Biological Blood Brain Brain region Brain-Derived Neurotrophic Factor Cells Childhood Clinical Corticosterone Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors DNA Methylation Development Disease susceptibility Epigenetic Process Exhibits Future Gene Cluster Gene Expression Gene Expression Profile Gene Targeting Genes Glucocorticoid Receptor Hippocampus (Brain)Histone Deacetylase Inhibitor Human Hypothalamic structure Impulsivity Inbreeding Individual Instruction Intervention Knowledge Laboratory mice Life Link Mental Depression Molecular Monoamine Oxidase A Mus Neurobiology Neurons Neurotransmitter Receptor Nucleic Acid Regulatory Sequences Outcome Measure Pathway interactions Peripheral Phenotype Pituitary Gland Promoter Regions Psychopathology Research Risk Risk Factors Role Stress Suicide Testing Therapeutic Intervention Time Tissue-Specific Gene Expression Tissues Tryptophan 5-monooxygenase Variant abuse neglect brain tissue complement system corticotropin releasing factor-binding protein density depressive symptoms design environmental enrichment for laboratory animals environmental intervention epigenetic variation experience glycogen synthase kinase 3 beta human RGS2 protein indexing infancy insight maternal separation molecular phenotype mouse model neuroimaging novel strategies postnatal promoter research study response serotonin 5 receptor serotonin transporter social suicidal behavior suicidal risk

项目摘要

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.

以忽视/虐待形式出现的童年逆境经历是未来自杀的主要风险因素