Abstract
Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.
Highlights
IntroductionSeveral clinical reports have noted that statins have been linked to sleep disturbances, including insomnia [2], while others report no impact on sleep [3,4,5]
Publisher’s Note: MDPI stays neutralStatins are among the most prescribed drugs worldwide due to their ability to decrease the risk for cardiovascular disease, the main global cause of morbidity and mortality [1].Several clinical reports have noted that statins have been linked to sleep disturbances, including insomnia [2], while others report no impact on sleep [3,4,5]
To determine whether Hmgcr activity is important in the regulation of sleep, the Drosophila pan-neuronal elav-GAL4 driver [19] was used to knockdown Hmgcr expression in fly neurons
Summary
Several clinical reports have noted that statins have been linked to sleep disturbances, including insomnia [2], while others report no impact on sleep [3,4,5]. The sleep homeostatic process is the primary regulator of the sleep–wake cycle. In Drosophila, several genes, neuronal circuits, and biological processes have been identified as being involved in the regulation of sleep [7,8,9,10]. These include a group of neurons that project to the with regard to jurisdictional claims in published maps and institutional affiliations
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