nad a22 4500 555222535 20190203201236.0 cr unu---uuuuu 190203s2018 xx s 000 0 eng 10.5167/uzh-165810 doi 10.3389/fncel.2018.00532 doi (ZORA)oai:www.zora.uzh.ch:165810 570 ddc 30687018 pmid High-altitude cognitive impairment is prevented by enriched environment including exercise via VEGF signaling [Elektronische Daten] [Christina Koester-Hegmann, Harkaitz Bengoetxea, Dmitry Kosenkov, Markus Thiersch, Thomas Haider, Max Gassmann, Edith M Schneider Gasser] openAccess eu-repo Exposure to hypobaric hypoxia at high altitude (above 2500 m asl) causes cognitive impairment, mostly attributed to changes in brain perfusion and consequently neuronal death. Enriched environment and voluntary exercise has been shown to improve cognitive function, to enhance brain microvasculature and neurogenesis, and to be neuroprotective. Here we show that high-altitude exposure (3540 m asl) of Long Evans rats during early adulthood (P48-P59) increases brain microvasculature and neurogenesis but impairs spatial and visual memory along with an increase in neuronal apoptosis. We tested whether enriched environment including a running wheel for voluntary exercise (EE) can prevent cognitive impairment at high-altitude and whether apoptosis is prevented. We found that EE retained spatial and visual memory at high altitude, and prevented neuronal apoptosis. Further, we tested whether vascular endothelial growth factor (VEGF) signaling is required for the EE-mediated recovery of spatial and visual memory and the reduction in apoptosis. Pharmacological inhibition of VEGF signaling by oral application of a tyrosine kinase inhibitor (Vandetanib) prevented the recovery of spatial and visual memory in animals housed in EE, along with an increase in apoptosis and a reduction in neurogenesis. Surprisingly, inhibition of VEGF signaling also caused impairment in spatial memory in EE-housed animals reared at low altitude, affecting mainly dentate gyrus microvasculature but not neurogenesis. We conclude that EE-mediated VEGF signaling is neuroprotective and essential for the maintenance of cognition and neurogenesis during high-altitude exposure, and for the maintenance of spatial memory at low altitude. Finally, our data also underlines the potential risk of cognitive impairment and disturbed high altitude adaption from the use of VEGF-signaling inhibitors for therapeutic purposes. Institute of Pharmacology and Toxicology zora Center for Integrative Human Physiology zora Institute of Veterinary Physiology zora angiogenesis zora neurogenesis zora neuroprotection zora spatial memory zora tyrosine kinase inhibitor zora visual memory zora Koester-Hegmann Christina joint author Bengoetxea Harkaitz joint author Kosenkov Dmitry joint author Thiersch Markus joint author Haider Thomas joint author Gassmann Max joint author Schneider Gasser Edith M. joint author Frontiers in Cellular Neuroscience 12:532 https://www.zora.uzh.ch/id/eprint/165810/1/Koester-Hegmann_fncel-12-00532_open_access.pdf text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora ZORA 856 40 https://www.zora.uzh.ch/id/eprint/165810/1/Koester-Hegmann_fncel-12-00532_open_access.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Koester-Hegmann Christina joint author ZORA 700 1- Bengoetxea Harkaitz joint author ZORA 700 1- Kosenkov Dmitry joint author ZORA 700 1- Thiersch Markus joint author ZORA 700 1- Haider Thomas joint author ZORA 700 1- Gassmann Max joint author ZORA 700 1- Schneider Gasser Edith M. joint author ZORA 773 0- Frontiers in Cellular Neuroscience 12:532 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article openAccess