Abnormal brain activity in rats with sustained hypobaric hypoxia exposure

Abstract

Background:Hypobaric hypoxia (HH) exposure at high altitudes can result in a decline in cognitive function, which may have a serious impact on the daily life of people who migrate to high altitudes. However, the specific HH-induced changes in brain function remain unclear. This study explored changes in brain activity in rats exposed to a sustained HH environment using functional magnetic resonance imaging (fMRI).Methods:Healthy male rats (8 weeks old) were randomly divided into a model group and a control group. A rat model of cognitive impairment induced by sustained HH exposure was established. The control and model groups completed training and testing in the Morris water maze (MWM). A two-sample t-test for between-group difference comparisons was performed. Repeated measures analyses of variance for within-group comparisons were performed and post-hoc comparisons were made using the Tukey test. Between-group differences in spontaneous brain activity were assessed using a voxel-wise analysis of resting-state fMRI (rs-fMRI), combined with analyses of the fractional amplitude of low frequency fluctuations (fALFF) in statistical parametric mapping.Results:In the MWM test, the escape latencies of the model group were significantly longer compared with those of the control group (control group vs. model group, day 1: 21.6 ± 3.3 s vs. 40.5 ± 3.4 s, t = –11.282; day 2: 13.5 ± 2.2 s vs. 28.7 ± 5.3 s, t = –7.492; day 3: 10.5 ± 2.8 s vs. 22.6 ± 6.1 s, t = –5.099; day 4: 9.7 ± 2.5 s vs. 18.6 ± 5.2 s, t = –4.363; day 5: 8.8 ± 2.7 s vs. 16.7 ± 5.0 s, t = –3.932; all P < 0.001). Within both groups, the escape latency at day 5 was significantly shorter than those at other time points (control group: F = 57.317, P < 0.001; model group: F = 50.718, P < 0.001). There was no within-group difference in average swimming speed (control group, F = 1.162, P = 0.956; model group, F = 0.091, P = 0.880). Within the model group, the time spent within the original platform quadrant was significantly shorter (control group vs. model group: 36.1 ± 5.7 s vs. 17.8 ± 4.3 s, t = 7.249, P < 0.001) and the frequency of crossing the original platform quadrant was significantly reduced (control group vs. model group: 6.4 ± 1.9 s vs. 2.0 ± 0.8 s, t = 6.037, P < 0.001) compared with the control group. In the rs-fMRI study, compared with the control group, rats in the model group showed widespread reductions in fALFF values throughout the brain.Conclusions:The abnormalities in spontaneous brain activity indicated by the fALFF measurements may reflect changes in brain function after HH exposure. This widespread abnormal brain activity may help to explain and to provide new insights into the mechanism underlying the impairment of brain function under sustained exposure to high altitudes.

Neuroprotective Effects of Moderate Hypoxia: A Systematic Review

“…Another EEG study in mice found decreased P300 amplitude following hypobaric, continuous 12.5-13.5% O 2 administered chronically for 14 days in addition to a reduction in working memory performance [70]. An fMRI study in rats found decreased resting-state activity after hypobaric continuous hypoxia administered chronically for 4 weeks (10% O 2 ) alongside impaired memory [64]. Finally, a structural MRI study showed reduced hippocampal volume in rats subjected to continuous high altitude living (4250 m corresponding to approx.…”

“…Of the 48 included animal studies, 28 (58.5%) observed adverse effects of hypoxia exposure [27][28][29]31,32,35,36,[38][39][40][41]46,47,49,50,57,59,[61][62][63][64]66,67,[69][70][71][72], while 18 studies (37.5%) reported beneficial effects [26,33,34,37,[42][43][44][45]48,51,53,55,56,58,60,65,68,73] and two studies (4%) found either no change in outcomes or mixed findings in both directions after hypoxia treatment [30,52].…”

“…Thirty-eight studies investigated the effects of moderate hypoxia exposure on cognitive functioning and anxiety-and depression-like behavior in rodents (see Table 2). Thirty-three studies examined hypoxia-related changes in hippocampal-dependent learning and memory performance, mostly assessed with the Morris water maze paradigm (27 of 33 studies) [30][31][32][34][35][36][38][39][40][41][42]44,45,50,51,[54][55][56][57][59][60][61][62][63][64][65]72]. Of these, 21 studies reported impaired learning and memory following various protocols with higher doses of hypoxia, including normobaric intermittent hypoxia (mainly 10% O 2 ) chronically administered for +10 h daily over 2-4 weeks, or hypobaric continuous hypoxia of 11-13% O 2 chronically administered over 4-12 weeks [31,32,35,36,[38][39][40][41]50,54,57,59,[61][62][63][64]…”

“…Seven studies further investigated the effects of hypoxia on working memory, using working-memory versions of maze paradigms and object recognition paradigms [38,49,56,60,61,64,70]. Of these, four detected impaired working memory performance following both hypobaric or normobaric hypoxia, involving continuous exposures of 10.5-13.5% O 2 chronically for 8-24 h daily over 2-4 weeks or intermittent 10% O 2 exposure chronically for two weeks [38,49,63,70].…”

“…Four studies studied the effects of hypoxia on the brain using in vivo neuroimaging approaches in animals [29,64,70,71]. One EEG study in rats found reduced theta and delta activity following hypobaric, continuous 14% O 2 chronically for 28 days [29].…”