Exercise hormone irisin is a critical regulator of cognitive function.

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

Diffusion tensor-MRI detects exercise-induced neuroplasticity in the hippocampal microstructure in mice.

BACKGROUND: Despite considerable research on exercise-induced neuroplasticity in the brain, a major ongoing challenge in translating findings from animal studies to humans is that clinical and preclinical settings employ very different techniques. OBJECTIVE: Here we aim to bridge this divide by using diffusion tensor imaging MRI (DTI), an advanced imaging technique commonly applied in human studies, in a longitudinal exercise study with mice. METHODS: Wild-type mice were exercised using voluntary free-wheel running, and MRI scans were at baseline and after four weeks and nine weeks of running. RESULTS: Both hippocampal volume and fractional anisotropy, a surrogate for microstructural directionality, significantly increased with exercise. In addition, exercise levels correlated with effect size. Histological analysis showed more PDGFRα+ oligodendrocyte precursor cells in the corpus callosum of running mice. CONCLUSIONS: These results provide compelling in vivo support for the concept that similar adaptive changes occur in the brains of mice and humans in response to exercise.