Temporal trajectories of novel object recognition performance in mice exposed to intermittent hypoxia

Abstract

Intermittent hypoxia is one of the major perturbations of sleep-disordered breathing and has been causally implicated in neurocognitive deficits. However, the reversibility of such deficits is unclear.Male C57BL/6J mice were exposed to either intermittent hypoxia or room air for 3-240 days, and then half were randomly selected and allowed to recover in normoxic conditions for the same duration of the previous exposure. A novel object recognition (NOR) test was performed.NOR performance was stable over time in room air. Intermittent hypoxia induced significant reductions in recognition index that progressed over the first 45 days and stabilised thereafter. Normoxic recovery of recognition index was essentially complete and indistinguishable from room air in mice exposed to shorter intermittent hypoxia times (<90 days). However, significant residual deficits emerged after normoxic recovery following prolonged intermittent hypoxia exposures (p<0.01). In addition, gradual attenuation of the magnitude of recovery in recognition index occurred with increasingly longer intermittent hypoxia exposures (MANOVA p<0.0001).Intermittent hypoxia during the resting period reduces NOR performance in a time-dependent fashion. Reversal of NOR performance deficits is unlikely after prolonged intermittent hypoxia duration. These findings suggest that early recognition of sleep apnoea and effective treatment are critical for restoration of the adverse cognitive effects of the disease.

Intermittent Hypoxia Severity in Animal Models of Sleep Apnea

“…The conventional settings used for applying intermittent hypoxia to animals include two major parameters, with one of them being the frequency of hypoxic events [which loosely corresponds to the clinical index of apnea-hypopnea index (AHI) recorded in polysomnographic studies of patients with OSA, Berry et al, 2018 ]. Setting the frequency of intermittent hypoxia to mimic different values of AHI is a relatively straightforward proposition, and different investigators have carried out animal experiments in which they modeled varying rates of hypoxic events such as to cover a wide range of AHI, e.g., from the highest events rates in OSA patients (60 events/h) to occasional events (2 events/h) (Almendros et al, 2013 ; Shiota et al, 2013 ; Dalmases et al, 2014 ; Jun et al, 2014 ; Briançon-Marjollet et al, 2016 ; Gozal et al, 2017 ). Moreover, at any given frequency of cycling it is also simple to prescribe different durations for the de-oxygenation and re-oxygenation phases within each cycle (Chodzynski et al, 2013 ; Lim et al, 2015 ).…”

Effect of age on the cardiovascular remodelling induced by chronic intermittent hypoxia as a murine model of sleep apnoea

“…Regarding the clinical and translational relevance of our current findings, we propose that young adult subjects with OSA will be predisposed to premature ageing, reinforcing the importance of early diagnosis and treatment, especially considering that the reversibility of vascular disease following CIH may be suboptimal at best. 7,47 Future studies are needed to elucidate the cellular and molecular changes associated with CIH-induced cardiovascular ageing to specifically identify putative therapeutic targets.…”

Sleep Apnoea and Early Antecedents of Adult Disease

“…These overall findings have suggested that the presence of long-standing disease may adversely affect the reversibility of its consequences, and preliminary experimental evidence in murine models appears to support such assumption and point to the possibility that the presence of some or all of the characteristic perturbations that constitute OSA may foster selective changes in the epigenome, some of which may become irreversible 14,15 .…”