Chronic Exposure to High Altitude: Synaptic, Astroglial and Memory Changes

Rupali Sharma,Daniel P Perl,Daniel P Perl,Bernard J Dardzinski,Bernard J Dardzinski,Xiufen Xu,Xiufen Xu,Dara L Dickstein,Dara L Dickstein,Nathan P Cramer,Nathan P Cramer,Diego Iacono,Diego Iacono,Diego Iacono,Diego Iacono,Erin K Murphy,Erin K Murphy,Zygmunt Galdzicki,Zygmunt Galdzicki,Zahra Adahman,Zahra Adahman,Bayley Perry,Bayley Perry

doi:10.1038/s41598-019-52563-1

Abstract

Long-term operations carried out at high altitude (HA) by military personnel, pilots, and astronauts may trigger health complications. In particular, chronic exposure to high altitude (CEHA) has been associated with deficits in cognitive function. In this study, we found that mice exposed to chronic HA (5000 m for 12 weeks) exhibited deficits in learning and memory associated with hippocampal function and were linked with changes in the expression of synaptic proteins across various regions of the brain. Specifically, we found decreased levels of synaptophysin (SYP) (p < 0.05) and spinophilin (SPH) (p < 0.05) in the olfactory cortex, post synaptic density−95 (PSD-95) (p < 0.05), growth associated protein 43 (GAP43) (p < 0.05), glial fibrillary acidic protein (GFAP) (p < 0.05) in the cerebellum, and SYP (p < 0.05) and PSD-95 (p < 0.05) in the brainstem. Ultrastructural analyses of synaptic density and morphology in the hippocampus did not reveal any differences in CEHA mice compared to SL mice. Our data are novel and suggest that CEHA exposure leads to cognitive impairment in conjunction with neuroanatomically-based molecular changes in synaptic protein levels and astroglial cell marker in a region specific manner. We hypothesize that these new findings are part of highly complex molecular and neuroplasticity mechanisms underlying neuroadaptation response that occurs in brains when chronically exposed to HA.

Highlights

Long-term operations carried out at high altitude (HA) by military personnel, pilots, and astronauts may trigger health complications
We found that during the training session, there was no significant difference in the amount of time HA mice spent freezing compared to sea level (SL) mice (Fig. 1A)
We found a decrease in the expression levels of post synaptic density−95 (PSD-95) (t = 2.570; p = 0.027, Fig. 5C), growth associated protein 43 (GAP43) (t = 4.199; p = 0.001, Fig. 5D), and glial fibrillary acidic protein (GFAP) (t = 4.323; p = 0.001, Fig. 5E) in HA mice compared to SL mice

Summary

Introduction

Long-term operations carried out at high altitude (HA) by military personnel, pilots, and astronauts may trigger health complications. Our data are novel and suggest that CEHA exposure leads to cognitive impairment in conjunction with neuroanatomically-based molecular changes in synaptic protein levels and astroglial cell marker in a region specific manner We hypothesize that these new findings are part of highly complex molecular and neuroplasticity mechanisms underlying neuroadaptation response that occurs in brains when chronically exposed to HA. To investigate the underlying molecular and related neuroadaptive effects of CEHA, we utilized our well-established and previously characterized mouse model of HA where animals are exposed to chronic HA (5000 m) for 12 weeks[13,19,21] and compared to mice kept at sea level (SL) Using this model we measured behavioral performance, synaptic morphological changes, and biochemical changes of different synaptic, astroglial and myelin proteins across different regions of the CNS (olfactory cortex, hippocampus, cerebellum and brainstem). All statistical analyses were carried out using Prism 7.00 software (GraphPad software, La Jolla, CA USA)

Methods

Results

Discussion

Conclusion