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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：
10661680
负责人：
MICHAEL L PLATT
金额：
$ 32.18万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661680
关键词：
Acute Address Affect Age Anatomy Animal Model Animals Anxiety Architecture Area Behavior 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 Health Histology Human Hurricane Impaired health Individual Intervention Island Knowledge Left Life Link Macaca Macaca mulatta Maps Measures Mediating Mediator 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 Predisposition 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 health behavioral impairment behavioral response biological adaptation to stress 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 neural circuit neurogenomics neuroinflammation neuron development neuronal growth neuroprotection nonhuman primate physical conditioning receptor density 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.

高通量和具有成本效益的测序技术的出现导致了最近的戏剧性变化。在确定精神健康综合征的遗传相关性方面取得进展。尽管取得了这一进展，生物学机制仍然知之甚少。关键挑战包括确定哪些变体与疾病病因有因果关系，这种变异如何与社会行为的变异相关，认知，以及这种变异如何与环境相互作用产生功能障碍。标准方法解决这些挑战的方法是研究小鼠和苍蝇等小动物模型，但这些模型受到以下因素的限制：他们简单的行为和认知能力以及潜在的神经回路差异，与人类相比。一个有希望的替代方法是定义多组学结构和神经解剖学与非人类灵长类动物的复杂社会行为相关，这些灵长类动物共享核心神经和遗传途径人类适应社会生活。这项研究的目标是确定大脑如何处理社会经验，以产生一个更好地了解对最终影响健康和福祉的生活事件的脆弱性和复原力。具体来说，我们将定量定义社会支持和社会脆弱性在自由放养的恒河猴圣地亚哥岛（波多黎各）的猕猴种群，并将评估这些之间的关联因素和灵长类动物大脑的多组结构和神经解剖学。我们将在典型的环境条件，但也将利用极端环境事件的发生，主要飓风，以评估在多种条件下的社会复原力。首先，我们将描述灵长类动物社会脑的神经基因组和调控景观及其对人类的影响。在基线慢性应激条件下的相关解剖学意义。我们将生成特定区域转录组和表观基因组的大脑区域与社会信息处理和牵连心理健康基因模型我们将联合收割机结合这些基因组数据与结构的详细措施，使用脑成像和组织学技术收集的连接和受体密度。的组合这些方法将帮助我们开发一个完全实现的生物模型，环境对社会表型的贡献以及它们的分子、结构和功能相互关联最后，我们将描述社会支持如何缓冲创伤性生活事件的影响，造成了飓风玛丽亚及其后果的严重和突然的压力经历。发展这一一种动物模型将使我们能够更有效地针对直接影响神经系统的干预措施。在各种心理健康综合征中，介导行为受损的回路。