Social regulation of oxidative stress in the brain

About This Grant

PROJECT SUMMARY The social environment can be a source of stress. Social stress is normal, but when persistent, it causes oxidative stress in the brain, which contributes to a variety of mental health and neurodegenerative diseases. Mitochondria could mediate the link between the social environment and oxidative stress as they are a major source of reactive oxygen species (ROS) and play a role in stress adaptation. Previous research has focused on chronic social defeat stress and resulting elevation in glucocorticoid levels, which causes oxidative stress in specific brain regions. Androgens modulate many metabolic responses, yet despite their responsiveness to social stressors and relevance to many age-related diseases, the role of androgenic signaling in regulating oxidative challenges in a social context is understudied. My goal is to study how androgens and social stress influence the regulation of oxidative stress in the brain by leveraging the highly social cichlid fish Astatotilapia burtoni, a well-established model system for neurogenomics and integrated animal behavior. Male A. burtoni exist as two reversible phenotypes: dominant and subordinate. Dominant males aggressively defend a territory, have high androgen levels, large gonads, and mate with females, while subordinate males are nonterritorial and reproductively suppressed. Territorial defense is physically and cognitively demanding for dominant individuals, while subordinate males experience social suppression and intimidation from higher ranking individuals. Females engage in aggressive competition for shelter and form distinct dominance hierarchies when housed in all-female groups, allowing us to study the effect of distinct social stressors in high- and low-ranking individuals of both sexes. The overarching goal of this five-year proposal is to assess how competition-induced social stress combined with androgen receptor signaling influences the regulation of oxidative balance in the brain. In Research Direction 1, we will define the effect of social stress and androgen receptor signaling on oxidative stress and mitochondrial function across different parts of the brain. To this end, we will integrate social manipulations with androgen receptor pharmacology to study how distinct social and metabolic stressors across the dominance hierarchy influence the regulation of oxidative stress in the brain. In Research Direction 2, we will determine how social experience and androgen receptor signaling influence protection against an acute oxidative insult to the brain using a validated hypoxia-reoxygenation paradigm. Our integrative approach provides an opportunity to discover unanticipated cytoprotective mechanisms in the brain against both chronic and acute stressors. The proposed activities will allow me to develop a research program aimed at dissecting variable strategies used to cope with stressful experiences to maintain organismal homeostasis. My research program may lead to novel insights into intervention strategies or therapeutic targets that reduce oxidative stress and improve effective recovery from oxidative challenges.