Exercise‐induced promotion of hippocampal cell proliferation requires β‐endorphin

Adult hippocampal neurogenesis is influenced by a variety of stimuli, including exercise, but the mechanisms by which running affects neurogenesis are not yet fully understood. Because β‐endorphin, which is released in response to exercise, increases cell proliferation in vitro , we hypothesized that it could exert a similar effect in vivo and mediate the stimula tory effects of running on neurogenesis. We thus analyzed the effects of voluntary wheel‐running on adult neurogenesis (proliferation, differentiation, survival/death) in wild‐type and β‐endorphin‐deficient mice. In wild‐type mice, exercise promoted cell proliferation evaluated by sacrificing animals 24 h after the last 5‐bromo‐2′‐deoxyuridine (BrdU) pulse and by using endogenous cell cycle markers (Ki67 and pH 3 ). This was accompanied by an increased survival of 4‐wk‐old BrdU‐labeled cells, leading to a net increase of neurogenesis. β‐Endorphin deficiency had no effect in sedentary mice, but it completely blocked the runninginduced increase in cell proliferation; this blockade was accompanied by an increased survival of 4‐wk‐old cells and a decreased cell death. Altogether, adult neurogenesis was increased in response to exercise in knockout mice. We conclude that β‐endorphin released during running is a key factor for exercise‐induced cell proliferation and that a homeostatic balance may regulate the final number of new neurons.—Koehl, M., Meerlo, P., Gonzales, D., Rontal, A., Turek, F. W., Abrous, D. N. Exercise‐induced promotion of hippocampal cell proliferation requires β‐endorphin. FASEB J. 22, 2253–2262 (2008)