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.
Highlights
Exposure to hypobaric hypoxia after ascent to high altitude causes cognitive impairment, in spatial and visuospatial information processing (Pagani et al, 1998; Virues-Ortega et al, 2004; Wilson et al, 2009; Nation et al, 2017), which involves the cornu ammonis (CA1) area of the hippocampal formation (Poucet et al, 2010) and the primary visual cortex (Prusky et al, 2004)
High-altitude exposure significantly increased the Hct from 43.6 ± 2.4 to 62.9 ± 1.9 in rats kept in standard laboratory conditions (SC), from 40.6 ± 1.6 to 60.5 ± 2.5 in rats kept in EE, and from 52.4 ± 5.1 to extremely high levels of 81.7 ± 2.4 in rats kept in EE receiving vascular endothelial growth factor (VEGF) inhibitor (EE + inh) (ANOVA, ∗∗∗∗P < 0.0001, Figure 2B)
We evaluated the impact of EE and VEGF signaling on spatial and visual memory, as well as on neovascularization, neurogenesis, and neuronal apoptosis after prolonged exposure to high altitude
Summary
Exposure to hypobaric hypoxia after ascent to high altitude causes cognitive impairment, in spatial and visuospatial information processing (Pagani et al, 1998; Virues-Ortega et al, 2004; Wilson et al, 2009; Nation et al, 2017), which involves the cornu ammonis (CA1) area of the hippocampal formation (Poucet et al, 2010) and the primary visual cortex (Prusky et al, 2004). One of the leading causes of memory dysfunction at high altitude is attributed to reductions in cerebral blood flow via the vascular network (Lawley et al, 2017), and hypoxia, leading to apoptosis and neuronal loss (Titus et al, 2007; Maiti et al, 2008). Evidence for neuronal protection of VEGF was provided by studies showing that inhibition of VEGF signaling, via either monoclonal antibodies or tyrosine kinase inhibition, which inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) (Noble et al, 2004), leads to impaired spatial memory and to a reduced number of neurons in rats (Pati et al, 2009; Bengoetxea et al, 2018)
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