Title: Chronic Intermittent but not Constant Hypoxia Decreases NAA/Cr Ratios in Neonatal Mouse Hippocampus and Thalamus

Chronic constant hypoxia and chronic intermittent hypoxia are known to have deleterious effects on the central nervous system. Due to the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity and this can be non-invasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either chronic constant hypoxia (CCH) where the FIO2 was maintained at 11% continuously or to chronic intermittent hypoxia (CIH) where the FIO2 was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 weeks demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus; which was reversed by a subsequent exposure to 4 weeks of normoxia. Meanwhile, mice exposed to 4 weeks of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases such as obstructive sleep apnea have the potential for inducing significant neurocognitive recovery in these patients.