Physical Activity Rescues Neuronal Proliferation in the Hippocampus after Isoflurane Exposure

To date, the etiology of postoperative cognitive dysfunction is unclear, and no treatment is available. One potential patho- and at the same time target mechanism for treatments is hippocampal neurogenesis. We investigated how isoflurane affects adult hippocampal neurogenesis and hypothesized that the pro-neurogenic stimulus of physical activity could remedy anesthesia-induced neurogenic changes and associated cognitive dysfunction.We exposed young adult mice to isoflurane (ISO), half of which had access to a running wheel (ISO-RW). Both groups were compared with a control condition (CTR; CTR-RW). Cell proliferation and survival in the dentate gyrus of the hippocampus were quantified histologically 48 hours and 3 weeks after anesthesia by bromodeoxyuridine incorporation. Cell phenotype was determined by expression of neuronal markers and the extent of continuous endogenous neuronal proliferation was estimated by the total number of doublecortin-positive cells. The Morris water maze was used to test hippocampus-dependent functions.Our results show that isoflurane differentially affects the developmental stages of newborn hippocampal cells, as evidenced by decreased proliferation of neuronal progenitor cells but intact neuronal survival and associated spatial memory performance. Physical activity attenuated neuronal changes by preventing the decline of newborn neuronal progenitor cells and increasing the extent of continuous endogenous neuronal proliferation in isoflurane-treated animals. In conclusion, isoflurane selectively impairs the proliferation of neurons but does not affect their survival or functionality. The observed adverse effects can be mitigated by physical activity, a cost-effective means of preventing the neurogenic consequences of general anesthesia.