Developmental ethanol exposure-induced sleep fragmentation predicts adult cognitive impairment

Abstract

Developmental ethanol exposure can lead to long-lasting cognitive impairment, hyperactivity, and emotional dysregulation among other problems. In healthy adults, sleep plays an important role in each of these behavioral manifestations. Here we explored circadian rhythms (activity, temperature) and slow-wave sleep in adult mice that had received a single day of ethanol exposure on postnatal day 7 and saline littermate controls. We tested for correlations between slow-wave activity and both contextual fear conditioning and hyperactivity. Developmental ethanol resulted in adult hyperactivity within the home cage compared to controls but did not significantly modify circadian cycles in activity or temperature. It also resulted in reduced and fragmented slow-wave sleep, including reduced slow-wave bout duration and increased slow-wave/fast-wave transitions over 24 hour periods. In the same animals, developmental ethanol exposure also resulted in impaired contextual fear conditioning memory. The impairment in memory was significantly correlated with slow-wave sleep fragmentation. Furthermore, ethanol treated animals did not display a post-training modification in slow-wave sleep which occurred in controls. In contrast to the memory impairment, sleep fragmentation was not correlated with the developmental ethanol-induced hyperactivity. Together these results suggest that disruption of slow-wave sleep and its plasticity are a secondary contributor to a subset of developmental ethanol exposure's long-lasting consequences.

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

“…As photic phase-resetting is the primary mechanism by which circadian rhythms are synchronized to the environment, this suggests that adolescent mice may be relatively resilient to the chronodisruptive effects of acute ethanol. This insensitivity is consistent with the only other study of which we are aware that examines the effect of developmental ethanol exposure on circadian endpoints, which reports changes in slow-wave sleep, but not circadian activity or temperature rhythms, in mice exposed to ethanol on postnatal day 7 (Wilson et al, 2016). It is also noteworthy that adolescent rats are initially less sensitive to ethanol-induced sleep disruption (Ehlers et al, 2013).…”

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Using a similar dose of alcohol (2.5 g/kg; administered twice over a 2 h interval) PAE paradigm, Smiley et al observed a reduction in total brain volume (~10%), including in frontal cortex neurons (parvalbumin and calretinin GABAergic neurons; ~30%) in PN72–89 mice (Smiley et al 2015). In a follow-up study using the same PAE paradigm, adult PAE mice exhibited hyper-activity in their home cages, reduced and fragmented slow-wave sleep, and reduced slow-wave sleep duration (Wilson et al 2016). Furthermore, PAE mice exhibited impaired contextual fear conditioning memory that was significantly correlated with slow-wave sleep fragmentation (Wilson et al 2016).…”

“…In a follow-up study using the same PAE paradigm, adult PAE mice exhibited hyper-activity in their home cages, reduced and fragmented slow-wave sleep, and reduced slow-wave sleep duration (Wilson et al 2016). Furthermore, PAE mice exhibited impaired contextual fear conditioning memory that was significantly correlated with slow-wave sleep fragmentation (Wilson et al 2016). Interestingly, mice with impairments in GABA A receptors (or their subunits) have learning and memory deficits, hyperactivity, and dysregulated sleep patterns, impairments reminiscent of mouse models of acute third trimester PAE (DeLorey et al 1998; Volgin 2008).…”

Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain

“…Such ethanol-induced brain damage in neonates results in long-lasting brain structural [ 24 , 25 , 27 , 29 ] and behavioral abnormalities [ 9 , 31 , 32 ]. Even one day of acute ethanol exposure, which induces robust apoptosis [ 10 , 11 ], results in abnormalities in cellular, structural, physiological, and behavioral levels in the adult brain [ 25 , 26 , 27 , 29 , 30 , 31 , 32 ].…”

“…For instance, binge-like ethanol exposure in early postnatal rodents during the period equivalent to the third trimester of human pregnancy induces robust neurodegeneration [ 7 , 8 , 9 , 10 , 11 ], because neurons are particularly vulnerable to environmental toxins during this period of heightened synaptogenesis [ 12 ]. This ethanol-induced neurodegeneration, which is associated with glial activation [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ] and elevation of pro- and anti-inflammatory cytokines [ 13 , 20 , 21 , 22 , 23 ], may result in long-lasting cellular, physiological, and neurobehavioral deficits [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. It is conceivable that ethanol-induced glial activation/neuroinflammation in animal models of FASD is involved in the long-lasting brain damage, as reported in various neurodegenerative diseases [ 33 ] and brain injuries [ 34 ].…”