Maternal Repetitive Hypoxia Prior to Mating Confers Epigenetic Resilience to Memory Impairment in Male Progeny

We showed previously in a mouse model of vascular cognitive impairment and dementia involving chronic cerebral hypoperfusion (CCH) that repetitive hypoxic conditioning (RHC) of both parents results in the epigenetic, intergenerational transmission of resilience to recognition memory loss in adult progeny, as assessed by the novel object recognition test. The present study was undertaken in the same model to determine whether RHC treatment of one or both parents is required to confer dementia resilience intergenerationally. We found inherited resilience to 3 months of CCH in males is maternally mediated (p = .006). Statistically, we observed a strong trend for the paternal germline to contribute as well (p = .052). We also found that, in contrast to what is widely observed in males, females display intact recognition memory (p = .001) after 3 months of CCH, revealing a heretofore unidentified sexual dimorphism with respect to cognitive impact during disease progression. Overall, results of our study strongly implicate epigenetic changes in maternal germ cells, induced by our repetitive systemic hypoxic stimulus, contributing to a modified differentiation program capable of establishing a dementia-resilient phenotype in adult male first-generation progeny.