Glymphatic system clears toxic metabolites from human brain especially beta amyloid and tau proteins. This system is most active during sleep and its impaired function predisposes to Alzheimer’s ds. Two explanations have been provided for its maximum expression during sleep-
- Silencing of locus ceruleus during NREM sleep(Science. 2013 October 18; 342(6156) )
- Circadian expression of aquaporin 4 channel
Our traditional understanding was that locus ceruleus firing decreases considerably during NREM sleep and totally stops during REM sleep. Locus ceruleus was mainly responsible for state of wakefulness.
A recent study have shown that locus ceruleus firing continues during NREM sleep (Int. J. Mol. Sci. 2022, 23, 5028. ). What role does locus ceruleus firing play during NREM sleep was not known. Locus ceruleus firing during NREM sleep leads to elevated norepinephrine levels during NREM sleep.
In a recent study (Cell. 2025 Jan 8:S0092-8674(24)01343-6. doi: 10.1016/j.cell.2024.11.027. ) it was shown that Norepinephrine oscillation frequency during NREM sleep predicts glymphatic clearance. This explains that locus ceruleus firing during NREM sleep facilitates Glymphatic clearance. This study also showed that sleep aid zolpidem suppresses norepinephrine oscillations and glymphatic flow which can increase the risk of neurodegeneration.
Zolpidem is very widely used hypnotic. In light of this new finding we need to reconsider our approach of commonly prescribing Zolpidem to treat Insomnia. Zolpidem is also known to cause Sleepwalking and sleep related eating disorders.