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.
This proposal focuses on how chronic and acutely stressful events ?get under the skin? to change physiology and alter mental health, and what biological or behavioral qualities make individuals more resilient or vulnerable to the negative health consequences of extreme life events. We propose to address these questions by capitalizing on our large database of behavioral, genomic, and neurobiological data collected from a research colony of free-ranging rhesus macaques (Macaca mulatta) that lived on Cayo Santiago Island, Puerto Rico, before and after Hurricane Maria devastated the island in September 2017. Our ability to combine rich behavioral data with cutting-edge genomic and neurobiological techniques arms us with an unprecedented opportunity to probe the genomic, epigenomic, and neuroanatomical mediators of traits linked to mental health in a human-relevant animal model.
