Sex-based study of chronic hypoxia-related vulnerability to depression: age effects

Risk for major depressive disorder (MDD) risk increases with aging. Later-life depression affects 12-40% of people over 65yrs old, with biological risk factors including female sex, systemic inflammation and cognitive deficits. Women exhibit 5-10 fold higher risk for later-life depression vs. men. Environmental factors can contrib- ute notably to mental health status in aging. Rates of MDD rise significantly with living at altitude. Chronic hypo- baric hypoxia (CH-hypoxia) exposure occurs at altitude. We established a novel sex-based translational model to study impact of CH-hypoxia on vulnerability to depression. After 2-3wks in CH-hypoxia (4,500ft,or 18% partial pressure of oxygen or ppO2) vs normal oxygen levels (sea level or 21%ppO2), young adult rats (2.5m old) exhibit symptoms of depression, anxiety, anhedonia and cognitive dysfunction. Females are particularly susceptible. Rats in CH-hypoxia exhibit poor brain bioenergetics and systemic inflammation (elevated serum interleukin 6 or IL6, an inflammatory cytokine). Rats in CH-hypoxia do not respond to most selective serotonin reuptake inhibitors (SSRIs), but show antidepressant-like response to bioenergetic compounds such as cyclocreatine. Systemic inflammation and brain hypometabolism are hallmarks of aging, implying that CH-hypoxia may act as a signifi- cant risk factor for later-life MDD, especially in women. Systemic inflammation is linked to SSRI inefficacy and treatment-resistant depression. In older MDD patients, elevated serum IL6 is linked to impaired cognitive func- tion. The means by which inflammatory mediators may promote a depressive phenotype is as yet unclear, but may involve impact on neurotrophic factors and hippocampal neurogenesis. We now propose studies utilizing this model to evaluate age and sex as biological variables for impact of CH-hypoxia on vulnerability to depres- sion. Impact on behavioral and molecular biomarkers of depression will be addressed, including impact on in- flammatory and bioenergetic pathways, cognitive deficits linked to MDD, and efficacy of therapeutics. Our cen- tral hypothesis is that aging will intensify the impact of CH-hypoxia on inflammatory and brain bioenergetic processes, to worsen depressive and cognitive symptoms, and reduce treatment efficacy, with females more susceptible. Rats at the age of young adults (2.5m), older adults (4m, 8m) or aging adults (18m) will be tested after housing in CH-hypoxia (4,500ft) vs. normal oxygen levels (sea level). In Aim 1, rats will be tested for de- pression-like and anxiety-like behaviors. In Aim 2, rats will be tested for cognitive function, including learning and memory, and cognitive bias. Rats will be sacrificed and brain/serum tested for bioenergetic compounds (creatine, ATP), inflammatory mediators (IL6, IL-1β, TNFα, CRP), BDNF and hippocampal neurogenesis. In Aim 3, young adults (2.5m) and aging adults (18m) in CH-hypoxia or sea level, will be tested for antidepressant-like effects of the SSRI fluoxetine and the bioenergetic compound cyclocreatine. These studies will lay the foundation for future research on the role of age and sex in CH-hypoxia-induced vulnerability to depression, and will allow us to explore novel therapeutics for later-life MDD based on the role of inflammatory and bioenergetic pathways.