Differential Sensitivity to Ethanol‐Induced Circadian Rhythm Disruption in Adolescent and Adult Mice

Abstract

Background Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether ethanol has similar effects on circadian regulation during adolescence. Methods General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12 h light, 12 h dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of ethanol (1.5 g/kg, i.p.) or equal volume saline 15 min prior to a 30-min light pulse at Zeitgeber Time 14 (2 h into the dark phase), then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age group received injections but no light pulse prior to DD. Results While adults showed the expected decrease in photic phase-delays induced by acute ethanol, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Conclusions Collectively, our results indicate that adolescent mice are less sensitive to the effect of ethanol on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults.

Sex Differences in Photic Entrainment and Sensitivity to Ethanol‐Induced Chronodisruption in Adult Mice After Adolescent Intermittent Ethanol Exposure

“…Studies of alcohol’s effects on circadian rhythms during development are hampered by the lack of research on developmental changes in rodents’ circadian rhythmicity, despite the fact that circadian activity measures translate easily between rodents and humans. We have recently begun to address this gap in the literature, reporting age-related changes in photic entrainment and larger phase-delays of circadian activity in adolescent mice compared to adults (Ruby et al, 2017), which is consistent with previous reports (Weinert et al, 1994, Weinert and Kompauerova, 1998) and supports one of the proposed mechanisms underlying eveningness in human adolescents (Hagenauer et al, 2009). We also observed insensitivity to the inhibitory effect of acute, moderate-dose ethanol on photic phase-resetting among adolescent mice, suggesting this as a permissive factor for adolescent drinking (Ruby et al, 2017).…”

“…We have recently begun to address this gap in the literature, reporting age-related changes in photic entrainment and larger phase-delays of circadian activity in adolescent mice compared to adults (Ruby et al, 2017), which is consistent with previous reports (Weinert et al, 1994, Weinert and Kompauerova, 1998) and supports one of the proposed mechanisms underlying eveningness in human adolescents (Hagenauer et al, 2009). We also observed insensitivity to the inhibitory effect of acute, moderate-dose ethanol on photic phase-resetting among adolescent mice, suggesting this as a permissive factor for adolescent drinking (Ruby et al, 2017). The present study aimed to characterize the effects of adolescent intermittent ethanol (AIE) exposure on circadian activity in mice both during adolescence and later, in adulthood.…”

“…Ethanol disrupts circadian timing by inhibiting both photic and nonphotic phase-resetting in several adult rodent species (Brager et al, 2010, Brager et al, 2011, Ruby et al, 2009a, Ruby et al, 2009b, Seggio et al, 2009). However, we recently reported that adolescent male mice are insensitive to the attenuating effect of ethanol on photic phase-resetting (Ruby et al, 2017), adding to the growing body of evidence that age of exposure determines in large part the effects and addictive potential of ethanol.…”

Paternal Preconception Every-Other-Day Ethanol Drinking Alters Behavior and Ethanol Consumption in Offspring

“…In contrast, in our prior studies with vapor exposure, sires were exposed only in adulthood (8–13 weeks of age; [30,31,37,40]). There are well documented differences in EtOH sensitivity [33,41,42] and stress responses [43,44,45] between adolescents and adults. It is unclear if this difference in experimental design impacted outcomes.…”

In Utero Alcohol Exposure and the Alteration of Histone Marks in the Developing Fetus: An Epigenetic Phenomenon of Maternal Drinking

“…Metabolic reactions produce redox potential that plays an important role in circadian rhythm functioning. Previous studies have suggested that ethanol exposure (both acute and chronic) alters several aspects of the circadian rhythm 36 - 39 .…”