Autophagy Mediates the Effects of Physical Exercise on Learning and Memory through Activation of Hippocampal BDNF

Abstract

Physical exercise is known to enhance learning and memory formation in the brain. These positive outcomes are mediated through the induction of the expression of a growth factor, brain derived neurotrophic factor (BDNF), in the hippocampus. BDNF promotes cognitive behaviors and induces brain plasticity. Previous work has also reported that stimulating autophagy can restore cognitive ability. In this study, we demonstrated that a short-term voluntary exercise paradigm is sufficient to upregulate autophagy in different brain regions in an age-dependent manner. This increase in autophagy was correlated with enhanced spatial learning and memory formation particularly in mature adult mice (10-week-old). Indeed, we showed that short-term voluntary wheel running increases the protein expression levels of the autophagy marker, protein light chain 3 (LC3B), in the hippocampus of 10-week-old mice. We used the Morris Water Maze to evaluate spatial learning and memory performance in mice belonging to different age groups. Our work revealed that 10-week-old exercising mice that were treated with a brain-permeable autophagy inhibitor during the behavioral test showed cognitive deficits in the maze suggesting that induction of autophagy is necessary for exercise-induced learning and memory formation. Interestingly, we also found that inhibition of autophagy in exercising 10-week-old mice decreases BDNF protein levels in the hippocampus as compared to the control exercising group. Overall, our results suggest that BDNF acts downstream of exercise-induced autophagy to promote learning and memory formation in mature adult mice. We found that this pathway is not conserved in juvenile or middle-aged mice.