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Neurogenomics of Vulnerability and Resilience to Mental Health Syndromes in Response to Extreme Life Events

应对极端生活事件时心理健康综合症的脆弱性和恢复力的神经基因组学

基本信息

批准号：
10430175
负责人：
MICHAEL L PLATT
金额：
$ 35.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10430175
关键词：
Acute Address Affect Age Anatomy Animal Model Animals Anxiety Architecture Area Behavioral Biological Biological Models Biology Brain Brain imaging Brain region Buffers Cardiovascular Diseases Chromatin Chronic Chronic stress Cognitive Complex Data Data Set Databases Development Diabetes Mellitus Diffusion Magnetic Resonance Imaging Disasters Disease Environment Etiology Event Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Models Genomics Genotype Goals Growth and Development function Health Histology Human Hurricane Impairment Individual Intervention Island Knowledge Left Life Link Macaca Macaca mulatta Maps Measures Mediating Mediator of activation protein Mental Depression Mental Health Mental disorders Methods Modeling Molecular Monkeys Morphology Mus Natural Disasters Neuroanatomy Neurobiology Neurodevelopmental Disorder Neuromodulator Pathway interactions Pattern Personal Satisfaction Phenotype Physiology Population Post-Traumatic Stress Disorders Primates Process Psychosocial Stress Puerto Rico Regulator Genes Research Sampling Severities Skin Social Behavior Social Environment Social isolation Social status Social support Stress Stressful Event Structure Symptoms Syndrome Techniques Technology Testing Tissue Harvesting Tissue Sample Variant Work acute stress addiction arm behavioral genomics behavioral health behavioral impairment behavioral response biological adaptation to stress brain behavior brain tissue causal variant cohort cost efficient depressive symptoms epigenome epigenomics experience fly genetic variant genome sequencing genomic data improved information processing insight low socioeconomic status mature animal multiple omics neural circuit neurogenomics neuroinflammation neuronal growth nonhuman primate physical conditioning receptor density relating to nervous system resilience response sex social social adversity social cognition social factors social integration social stress social vulnerability stressor trait transcriptome traumatic event whole genome

项目摘要

The emergence of high-throughput and cost-efficient sequencing technologies has led to dramatic recent progress in identifying genetic correlates of mental health syndromes. Despite this progress, the underlying biological mechanisms remain poorly understood. Critical challenges include determining which variants are causally related to disease etiology, how this variation is associated with variation in social behavior and cognition, and how this variation interacts with the environment to produce dysfunction. The standard approach to address these challenges is to study small animal models like mice and flies, but such models are limited by their simple behavioral and cognitive repertoire and potential differences in the underlying neural circuitry, compared with humans. A promising alternative is to define the multi-omic architecture and neuroanatomy associated with complex social behavior in nonhuman primates, which share core neural and genetic pathways with humans adapted to social life. The goal of the proposed research is to identify how the brain processes social experiences to produce a greater understanding of vulnerability and resilience to life events that ultimately affect health and well-being. Specifically, we will quantitatively define social support and social vulnerability in the free-ranging rhesus macaque population of Cayo Santiago Island (Puerto Rico) and will assess the associations between these factors and the multi-omic architecture and neuroanatomy of the primate brain. We will do so under typical environmental conditions but will also take advantage of the occurrence of an extreme environmental event, a major hurricane, to evaluate social resilience in multiple conditions. First, we will describe the neurogenomic and regulatory landscape in the primate social brain and its associated anatomical implications under baseline chronic stress conditions. We will generate region specific transcriptomes and epigenomes for brain areas associated with social information processing and implicated in mental health genetic models. We will combine these genomic data with detailed measures of structural connectivity and receptor densities collected using brain imaging and histology techniques. The combination of these approaches will help us develop a fully-realized biological model that recapitulates the genetic and environmental contributions to social phenotypes as well as their molecular, structural, and functional correlates. Finally, we will delineate how social support buffers the impact of a traumatic life event and the resulting severe and sudden stressful experiences of Hurricane Maria and its aftermath. Development of this type of animal model will permit us to more effectively target interventions that directly impact the neural circuits mediating behaviors impaired in a variety of mental health syndromes.

高通量和成本效益的测序技术的出现导致了最近的戏剧性