Neuropathophysiological deficits in a mouse model of high altitude exposure
Nathan P. Cramer1,2,, Alexandru Korotcov2,3, Asamoah Bosomtwi2,3, Xiufen Xu1,2, Derek Holman1,4, Scott Jones2,3, Andrew Hoy2,3, Bernard J. Dardzinski2,3, Zygmunt Galdzicki1,2,*
1Department of Anatomy, Physiology and Genetics, 2Center for Neuroscience and Regenerative Medicine, 3Department of Radiology and Radiological Sciences, 4Molecular Cell Biology Graduate Program, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD
Prolonged exposure to extreme environmental conditions can produce maladaptive physiological changes with long-lasting functional and behavioral deficits. However, the underlying pathophysiological mechanisms that contribute to persistent neurobehavioral deficits are not well understood. We investigated the effects of chronic exposure (1 to 8 months) to a simulated high altitude (HA) of 5000 meters in mice using in vivo magnetic resonance imaging (MRI). These studies were combined with examination of vasculature remodeling, microglia activation status and electrophysiological assessment of the corpus callosum. Hippocampal dependent memory formation and retention was tested using a fear conditioning paradigm. In order to understand the gene regulation changes underlying adaptive changes, we performed transcriptomics analysis on hippocampal and amygdalar tissues. All investigations were made in comparison to age matched sea level (SL) controls. In vivo MRI showed that exposure to HA for 1 to 8 months caused significant remodeling of the cerebrovascular system and corpus callosum consistent with pro- and maladaptative responses. Neuropathological examination of HA mice revealed significant angiogenesis, enhanced microglia activation and demyelination in the corpus callosum that was coupled with altered axonal excitability. Deficits in hippocampal function and the transcriptome were observed in HA mice consistent with angiogenesis, changes in brain inflammatory signaling and abnormal myelination. Chronic exposure to hypobaric-hypoxia triggers maladaptation causing cognitive deficits suggesting potential adverse impacts of staying or traveling at high altitude.
Funding: Supported by AFMSA, DoD; USUHS Program Project; CHIRP (NHLBI/NIH and USUHS), DoD for CNRM. Disclaimer: The views expressed here are those of the author(s) and do not reflect the official policy or position of the U.S. government or DoD.