High-Altitude Cognitive Impairment Is Prevented by Enriched Environment Including Exercise via VEGF Signaling

Abstract

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.

Selection Signatures Analysis Reveals Genes Associated with High-Altitude Adaptation in Tibetan Goats from Nagqu, Tibet

“…Angiogenesis is one of the key mechanisms of high-altitude adaptation [ 36 , 37 ]. Remarkably, FGF2 (fibroblast growth factor 2) ( di value = 10.53), one of the fibroblast growth factor family members ( FGFs) [ 38 ], has been proved as an angiogenic growth factor [ 39 ].…”

Possible Neuroprotective Mechanisms of Physical Exercise in Neurodegeneration

“…PE not only affects the activity of different brain cells, but also determines their survival and death. Recent evidence in a Long Evans rat model based study showed that voluntary exercise, in addition to enriched environment improves cognitive function, promoted neurogenesis and brain microvasculature in these rats exposed to hypobaric hypoxia at high altitudes by mediating VEGF signaling [ 111 ]. In a Wistar rat model, it was demonstrated that early PE in childhood and adolescence induces long term morphological alterations in hippocampal and cortical neurons even during the sedentary period of rats [ 112 ].…”

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

“…Abnormal VEGF signaling caused by diabetes can lead to vascular dysfunction and pathological vessel remodeling, leading to vascular occlusion and insufficient blood supply[ 42 - 45 ]. Meanwhile, some studies found that the inhibition of VEGF signaling affected hippocampal dentate gyrus microvasculature and caused impairment in spatial memory[ 46 ]. Therefore, the decreased expression of VEGF in the late stage of diabetes led to hypoperfusion in the hippocampus, as found in the present study, leading to cognitive abnormalities.…”