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

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Acute stress and chronic adversity affect biological systems at multiple levels, contributing to diverse mental and physical health outcomes. Yet, the mechanisms through which these stressors impact health—and the factors that foster resilience or increase vulnerability—are not well understood. The free-ranging rhesus macaques (Macaca mulatta) on Cayo Santiago island offer a unique natural experiment. In 2017, they experienced a Category 4 hurricane, followed by acute deprivation of food and water (later restored) and chronic deforestation, which led to sustained higher temperatures. Building on our prior R01- MH118203 support, we will use this setting to investigate how environmental stressors affect the brain. Our previous work established a comprehensive biobank from macaques with varied social status and connections, sampled before and after the hurricane. We found that social support protects against both chronic adversity (e.g., low social status) and acute trauma (e.g., natural disasters), with strong links to health, aging, and survival. With renewed support, we aim to expand these findings by examining molecular and anatomical variations in brain pathways associated with social connectedness, adversity, and stress. First, we will quantify the hurricane's short-term effects on brain health by comparing cohorts sampled before and shortly after the event. Using MRI and molecular data, we will assess the impact of social environment and hurricane exposure on brain phenotypes, identify regions vulnerable to hurricane stress, and examine whether hurricane-exposed animals show adverse molecular and neuroanatomical changes. We hypothesize that animals with higher social capital–the combination of social connections and social status–will demonstrate greater resilience, with social capital modulating molecular mechanisms that shape neural circuits. Next, we will analyze animals sampled in the following years to explore how social environment and hurricane exposure, combined with long-term environmental changes, influence brain health. Finally, we will prospectively sample animals exposed only to the altered post-hurricane environment to distinguish the effects of surviving a disaster from those of living in a chronically degraded environment. This project will precisely map the structural and molecular pathways by which social capital fosters resilience, a depth unachievable in pre-mortem human studies across lifespan-relevant timescales. The behavioral and biological similarities between macaques and humans endow this study with strong translational potential for addressing anxiety, depression, and related health impacts—crucial priorities for NIMH (NOT-MH- 18-058).