Skeletal muscle TFEB overexpression does not increase neurogenesis markers in the young female hippocampus.

Abstract

Adult hippocampal neurogenesis (AHN), the process in which new neurons are formed in the dentate gyrus of the hippocampus, declines with age and is highly responsive to voluntary wheel running in mice. This exercise-activated increase in AHN is believed to contribute to the cognitive and neurotrophic benefits of exercise on the aging and neurodegenerative disease-afflicted brain. However, our current understanding of the decline in AHN remains male-centric, with very few studies examining the effects of age and/or running on AHN in the female brain. Our lab has recently shown that skeletal muscle-specific overexpression of Transcription Factor E-B (TFEB), a master regulator of lysosomal and mitochondrial function, mimics many of the neuroprotective benefits of exercise during aging and in the context of Alzheimer's disease (AD) pathologies, but the effect of muscle-TFEB overexpression on AHN was unknown. Here we report that female AHN declines in a similar timeline as to what has been reported for the male hippocampus, following a precipitous decline at around 3 months of age that culminates at around 8 months of age. Furthermore, we report that muscle-TFEB overexpression does not prevent this age-associated decrease in AHN, suggesting that the neuroprotective benefits observed in our muscle-TFEB model are independent of AHN.