The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity.

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.

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.

The coronavirus disease 2019 (COVID-19) outbreak in North, Central, and South America has become the epicenter of the current pandemic. We have suggested previously that the infection rate of this virus might be lower in people living at high altitude (over 2,500 m) compared to that in the lowlands. Based on data from official sources, we performed a new epidemiological analysis of the development of the pandemic in 23 countries on the American continent as of May 23, 2020. Our results confirm our previous finding, further showing that the incidence of COVID-19 on the American continent decreases significantly starting at 1,000 m above sea level (masl). Moreover, epidemiological modeling indicates that the virus transmission rate is lower in the highlands (>1,000 masl) than in the lowlands (<1,000 masl). Finally, evaluating the differences in the recovery percentage of patients, the death-to-case ratio, and the theoretical fraction of undiagnosed cases, we found that the severity of COVID-19 is also decreased above 1,000 m. We conclude that the impact of the COVID-19 decreases significantly with altitude.

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation (MIA) based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased nicotinamidadenindinucleotid (NADH)- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

Several neurodevelopmental disabilities are strongly associated with alterations in GABAergic transmission, and therapies to stimulate its normal development are lacking. Erythropoietin (EPO) is clinically used in neonatology to mitigate acute brain injury, and to stimulate neuronal maturation. Yet it remains unclear whether EPO can stimulate maturation of the GABAergic system. Here, with the use of a transgenic mouse line that constitutively overexpresses neuronal EPO (Tg21), we show that EPO stimulates postnatal GABAergic maturation in the hippocampus. We show an increase in hippocampal GABA-immunoreactive neurons, and postnatal elevation of interneurons expressing parvalbumin (PV), somatostatin (SST), and neuropeptide Y (NPY). Analysis of perineuronal net (PNN) formation and innervation of glutamatergic terminals onto PV+ cells, shows to be enhanced early in postnatal development. Additionally, an increase in GABA_Aergic synapse density and IPSCs in CA1 pyramidal cells from Tg21 mice is observed. Detection of EPO receptor (EPOR) mRNA was observed to be restricted to glutamatergic pyramidal cells and increased in Tg21 mice at postnatal day (P)7, along with reduced apoptosis. Our findings show that EPO can stimulate postnatal GABAergic maturation in the hippocampus, by increasing neuronal survival, modulating critical plasticity periods, and increasing synaptic transmission. Our data supports EPO’s clinical use to balance GABAergic dysfunction. Visual Abstract