Treatment of mitochondrial disturbances due to early life adversity in mice results in restoration of complex I activity and normal reward behavior

The environment experienced by children, such as exposure to chronic early life adversity (ELA), increases lifespan brain disorder risk. The mechanisms that link ELA exposure to functional brain disruptions are not well understood. A limited-bedding and nesting paradigm, in which ELA is induced in mouse pups over the first postnatal week through disruption of maternal care, is characterized by limited resources, environment unpredictability, and disruption of reward and cognitive behaviors. Studies using this model demonstrated sex-selective alterations in hippocampal mitochondrial-associated proteins in response to ELA compared to care as usual (CAU). Further, oxidative phosphorylation (OXPHOS) capacity and complex I activity are increased in ELA juveniles, yet decreased in adults, with the impact of ELA moderated by sex in female adults. Given that altered mitochondrial function is a key mediator in metabolic adaptations, the goal of the present study was to evaluate the possibility of reversing mitochondrial dysfunction and the anhedonia that accompanies ELA by addressing oxidative stress. Treatment with the antioxidant MitoQ began at weaning and extended to 3 months. Measures of complex I activity demonstrated full recovery in adults. Female-specific deficits in the sucrose preference task, which is a measure of rewarding behavior in rodents, also exhibited recovery, with preference for sucrose comparable to that of CAU mice. These data indicate that mitochondrial health is one component of responses to early life adversity that has lifespan implications, but with the capacity to recover normal functioning in adults. Significance Statement Chronic early life stress in humans and animals leads to enduring functional changes to brain circuitry and behavior. An emerging concept involves the adaptation of mitochondria to address new energy demands as a primary cellular response to chronic stress. Long-term disruptions lead to oxidative stress, anhedonia and cognitive deficits. To determine if direct treatment of oxidative stress can mitigate adult dysfunction, an 8-week regimen of an antioxidant was administered to post-weaning mice that were raised early postnatally in an environment that disrupts predictable maternal care. Complex I mitochondrial energetics and sucrose preference were restored to levels comparable to mice raised in care as usual conditions, demonstrating a link between mitochondrial health and functional outcomes.