Orexin A ameliorates high altitude induced memory retrieval impairment via BDNF/TrkB and PI3K/AKT/mTOR signaling pathways.

High-altitude hypoxia induces cognitive impairment, with memory retrieval dysfunction being a predominant manifestation. The hypothalamus, prefrontal cortex, and hippocampus are key brain regions implicated in the formation of cognition. Orexin A neurons, primarily localized in the lateral hypothalamus, project extensively to various brain regions such as the prefrontal cortex and hippocampus. By modulating key signaling pathways, they play a critical role in learning and memory formation. Furthermore, orexin A also contributes to the modulation of cognitive functions by regulating microglial activation in the hippocampus. This study aims to elucidate the involvement and underlying molecular mechanisms of orexin A in hypoxia-induced memory retrieval deficits at high altitude. Utilizing Morris water maze, we evaluated the degree of memory retrieval impairment in wild-type and orexin A transgenic rats following 24 h of simulated hypoxia at 5 000 m and 7 000 m, combined with qRT-PCR and Western blot analyses of cortical orexin A, BDNF/TrkB, PI3K/AKT/mTOR signaling pathways and downstream inflammatory factors, alongside immunohistochemical assessment of hippocampal microglial activation. Behavioral tests revealed that higher altitudes are associated with a more severe decline in memory retrieval ability, which correlates with reduced cortical expression of orexin A, BDNF and TrkB. Notably, orexin A transgenic rats exhibited improved memory performance under hypoxic conditions, accompanied by upregulated BDNF/TrkB and PI3K/AKT/mTOR signaling, decreased IL-1β and IL-6 levels, elevated acetylcholine concentrations, and attenuated microglial activation compared to wild-type controls. These findings demonstrate that hypoxia-mediated orexin A downregulation contributes to high altitude memory impairment, highlighting orexin A's therapeutic potential for preventing cognitive dysfunction in high altitude environments.