Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%${\dot{V}}_{\mathrm{O}2\text{peak}}$) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3−neocortical functional connectivity. Significance Our previous work has shown that mild physical exercise can promote better memory in rodents. Here, we use functional MRI in healthy young adults to assess the immediate impact of a short bout of mild exercise on the brain mechanisms supporting memory processes. We find that this brief intervention rapidly enhanced highly detailed memory processing and resulted in elevated activity in the hippocampus and the surrounding regions, as well as increased coupling between the hippocampus and cortical regions previously known to support detailed memory processing. These findings represent a mechanism by which mild exercise, on par with yoga and tai chi, may improve memory. Future studies should test the long-term effects of regular mild exercise on age-related memory loss.

Significance: Muscle glycogen fuels exercising muscles to sustain endurance capacity. The brain also stores glycogen in astrocytes to produce lactate as an energy source transported to active neurons via the monocarboxylate transporter MCT2. Although physical exercise activates brain neurons and increases their energy demand, the energetic role of astrocytic glycogen in the exercising brain remains unknown. To address this issue, we used a rat model of prolonged exhaustive exercise, microwave irradiation of brains, metabolomics, and intracerebroventricular injection of inhibitors of glycogenolysis and MCT2. Our findings provide direct evidence that lactate derived from astrocytic glycogen fuels the prolonged-exercising brain to maintain endurance capacity. This new perspective on brain energetics during endurance exercise could lead to better strategies for endurance performance.

The mammalian brain contains neural stem cells (NSCs) that enable continued neurogenesis throughout adulthood. However, NSC function and/or numbers decline with increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3 promote NSC differentiation in a paracrine manner. Here, we show that both the levels of Wnt3 protein and the number of Wnt3‐secreting astrocytes influence the impairment of adult neurogenesis during aging. The age‐associated reduction in Wnt3 levels affects the regulation of target genes, such as NeuroD1 and retrotransposon L1, as well as the expression of Dcx, which is located adjacent to the L1 loci. Interestingly, the decline in the extrinsic Wnt3 levels and in the intracellular expression of the target genes with aging was reversible. Exercise was found to significantly increase de novo expression of Wnt3 and thereby rescue impaired neurogenesis in aged animals. Furthermore, the chromatin state of NeuroD1, L1, and the L1 loci near Dcx changed relative to Wnt3 levels in an age‐ or stimulus‐associated manner. These results suggest that the regulation of paracrine factors plays a critical role in hippocampal aging and neurogenesis.—Okamoto, M., Inoue, K., Iwamura, H., Terashima, K., Soya, H., Asashima, M., Kuwabara, T. Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J. 25, 3570–3582 (2011). www.fasebj.org