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Hypobaric Hypoxia (HH) is an established risk factor for various neuro-physiological perturbations including cognitive impairment. The origin and mechanistic basis of such responses however remain elusive. We here combined systems level analysis with classical neuro-physiological approaches, in a rat model system, to understand pathological responses of brain to HH. Unbiased ‘statistical co-expression networks’ generated utilizing temporal, differential transcriptome signatures of hippocampus—centrally involved in regulating cognition—implicated perturbation of Glio-Vascular homeostasis during early responses to HH, with concurrent modulation of vasomodulatory, hemostatic and proteolytic processes. Further, multiple lines of experimental evidence from ultra-structural, immuno-histological, substrate-zymography and barrier function studies unambiguously supported this proposition. Interestingly, we show a significant lowering of H2S levels in the brain, under chronic HH conditions. This phenomenon functionally impacted hypoxia-induced modulation of cerebral blood flow (hypoxic autoregulation) besides perturbing the strength of functional hyperemia responses. The augmentation of H2S levels, during HH conditions, remarkably preserved Glio-Vascular homeostasis and key neuro-physiological functions (cerebral blood flow, functional hyperemia and spatial memory) besides curtailing HH-induced neuronal apoptosis in hippocampus. Our data thus revealed causal role of H2S during HH-induced early Glio-Vascular dysfunction and consequent cognitive impairment., Highlights • Glio-Vascular dysfunction temporally precedes Hypobaric Hypoxia (HH) induced neuro-pathological effects. • Exposure to HH significantly lowers the levels of H2S in brain. • Augmentation of H2S, utilizing its donor, preserves Glio-Vascular homeostasis and curtails HH-induced memory impairment. The exposure to Hypobaric Hypoxia (HH) environment (such as that encountered by humans at high altitude) culminates in cognitive impairment in an altitude- and duration-dependent manner. The mechanistic basis for such effects, however, remains elusive. Our present study showed that HH-induced neuro-pathological perturbations are temporally preceded by Glio-Vascular dysfunction and are concomitant with lowered levels of gaseous messenger, H2S, in brain. The maintenance of H2S levels (utilizing a specific donor, NaHS) during hypoxia curtailed HH-induced brain-vascular dysfunction and ensuing neuro-pathological effects (on spatial memory). Interestingly, identification of origin of disease in the present study effectively revealed a possible interventional strategy.