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

高通量和低成本测序技术的出现导致了最近戏剧性的 识别精神健康综合征的遗传相关性的进展。尽管取得了这些进展，但潜在的 生物学机制仍然知之甚少。关键挑战包括确定哪些变种是 与疾病病因学的因果关系，这种变异如何与社会行为和 认知，以及这种变异如何与环境相互作用而产生功能障碍。标准方法 要应对这些挑战，就需要研究老鼠和苍蝇等小动物模型，但这些模型受到以下限制 它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。一种有希望的替代方案是定义多组体结构和神经解剖学 与非人类灵长类的复杂社会行为有关，这些灵长类共享核心神经和遗传途径 人类适应了社会生活。 这项拟议的研究的目标是确定大脑是如何处理社交经历来产生 更好地理解对最终影响健康和福祉的生活事件的脆弱性和复原力。 具体地说，我们将定量定义自由放养恒河猴的社会支持和社会脆弱性 卡约圣地亚哥岛(波多黎各)的猕猴种群，并将评估它们之间的联系 因素和灵长类大脑的多组体结构和神经解剖学。我们将在典型情况下执行此操作 环境条件，但也将利用极端环境事件的发生， 大飓风，以评估社会在多种情况下的韧性。 首先，我们将描述灵长类社会脑中的神经基因组和调节图景及其 基线慢性应激条件下的相关解剖学意义。我们将生成特定于地区的 与社会信息处理相关的大脑区域的转录本和表观基因组 心理健康遗传模型。我们将把这些基因组数据与详细的结构测量相结合 使用脑成像和组织学技术收集连接性和受体密度。这两种技术的结合 这些方法将帮助我们开发一种完全实现的生物模型，它概括了遗传和 环境对社会表型的贡献及其分子、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以及 飓风玛丽亚及其后果带来的严重和突如其来的压力经历。这方面的发展 动物模型的类型将使我们能够更有效地针对直接影响神经的干预措施 在各种精神健康综合症中，调节行为受损的回路。

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.