Abstract
Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7–9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28–42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II–V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking.
Highlights
Alcohol binge drinking is highly prevalent in teenagers [1] and is associated with high costs to global health and economy [2]
This same dose, route, and pattern of alcohol exposure during adolescence does not elicit measurable changes in glial cell number in the medial prefrontal cortex (mPFC) of female rats, but it has been shown to cause long-term effects on myelin in the prefrontal cortex, including downregulated myelin proteins and aberrant compaction of myelin sheaths in adult female mice [14]. These studies demonstrate the ability of high doses of alcohol to impact myelin proteins and white matter, but it should be noted that the exposure to alcohol was involuntary. This is an important factor to consider, as we have found that binge-like alcohol injections during adolescence can lead to lower baseline levels of alcohol drinking in adulthood, whereas drinking in adolescence can lead to higher levels of relapse after short periods of abstinence in adulthood [15]
Onset drinking has been linked to increased mental health risk and alcohol use disorder [38], and the present findings in conjunction with previous studies suggest that alcohol may perturb myelination of axons in prefrontal circuits during adolescence to drive some of these increased risks
Summary
Alcohol binge drinking is highly prevalent in teenagers [1] and is associated with high costs to global health and economy [2]. Brain Sci. 2019, 9, 167 reduction in functional anisotropy (white matter integrity) in major white matter frontal pathways when compared to controls [6,7,8]. These effects, in turn, are associated with a higher risk of developing alcohol dependence in adulthood [9,10]. While these human studies allow us to observe correlations between alcohol and myelin, they cannot directly test causal relationships
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