Sleep Modulates Alcohol Toxicity in Drosophila

Abstract

Alcohol abuse is a significant public health problem. While considerable research has shown that alcohol use affects sleep, little is known about the role of sleep deprivation in alcohol toxicity. We investigated sleep as a factor modulating alcohol toxicity using Drosophila melanogaster, a model for studies of sleep, alcohol, and aging. Following 24 h of sleep deprivation using a paradigm that similarly affects males and females and induces rebound sleep, flies were given binge-like alcohol exposures. Sleep deprivation increased mortality, with no sex-dependent differences. Sleep deprivation also abolished functional tolerance measured at 24 h after the initial alcohol exposure, although there was no effect on alcohol absorbance or clearance. We investigated the effect of chronic sleep deprivation using mutants with decreased sleep, insomniac and insulin-like peptide 2, finding increased alcohol mortality. Furthermore, we investigated whether pharmacologically inducing sleep prior to alcohol exposure using the GABAA-receptor agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) mitigated the effects of alcohol toxicity on middle-aged flies, flies with environmentally disrupted circadian clocks, and flies with short sleep. Pharmacologically increasing sleep prior to alcohol exposure decreased alcohol-induced mortality. Thus, sleep prior to binge-like alcohol exposure affects alcohol-induced mortality, even in vulnerable groups such as aging flies and those with circadian dysfunction.

Breaking free from the clock’s tyranny restores memory to brain damaged flies

“…Thus, as a stringent test of sleep's capacity to restore function in significantly compromised brains, we intensified sleep in flies with MB ablations and analyzed Short-Term Memory (STM) using the APS, and Long-Term Memory (LTM) using courtship conditioning. To enhance sleep, we employed two independent and widely utilized approaches: Gaboxadol administration (4,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55), and genetically activating sleep promoting neurons (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). Newly hatched Canton-S (Cs) larvae were fed Hydroxyurea (HU) to eliminate the Kenyon cells forming the α/β, α'/β' and most of the γ lobes (39).…”

Alcohol tolerance encoding in sleep regulatory circadian neurons in Drosophila

“…Additionally, a subset of histone demethylases of JmjC class regulate both sleep and rapid tolerance (Pinzón et al, 2017; Shalaby et al, 2018). Sleep deprivation for 1 day prior to tolerance induction appears to increase rapid tolerance measured at 4 hr, but it reduces tolerance at 24 hr (De Nobrega et al, 2022). However, rapid tolerance does not appear to be regulated by circadian time (van der Linde and Lyons, 2011; De Nobrega and Lyons, 2016).…”

Alcohol sensitivity and tolerance encoding in sleep regulatory circadian neurons in Drosophila

“…Additionally, a subset of histone demethylases of the JmjC class regulate both sleep and rapid tolerance. 60,61 Sleep deprivation for 1 day prior to tolerance induction appears to increase rapid tolerance measured at 4 h, but it reduces tolerance at 24 h. 62 However, rapid tolerance does not appear to be regulated by circadian time. 63,64 Thus, current evidence supports a role for ethanol in regulating sleep that is causally connected to rapid tolerance development, however the clock does not appear to reciprocally regulate rapid tolerance development.…”

“…Additionally, a subset of histone demethylases of the JmjC class regulate both sleep and rapid tolerance 60,61 . Sleep deprivation for 1 day prior to tolerance induction appears to increase rapid tolerance measured at 4 h, but it reduces tolerance at 24 h 62 . However, rapid tolerance does not appear to be regulated by circadian time 63,64 .…”