Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats

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.

Sex Differences in the Neurobiology of Alcohol Use Disorder

“… 133 , 134 Likewise, animal studies show that voluntary alcohol exposure during adolescence decreases the density of myelinated axons in the anterior cingulate subregion of the medial prefrontal cortex, with higher adolescent drinking levels predicting lower working memory performance later in adulthood. 30 Reduced myelin density was not observed in female rats after adolescent binge drinking, 31 which corresponds with another study in mice showing that high doses of alcohol reduce myelin genes to a lesser extent in adolescent females compared to males. 135 …”

“…In both cases, these microstructural alterations have potential to negatively impact the speed and integrity of neural transmission, which is essential for effective communication within and between cortical and subcortical structures. 31 Altogether these studies show alcohol affects cortical circuits that are important for executive functioning and behavioral control, and does so to a greater extent in males than in females.…”

“…Despite more robust effects in males, examination of myelinated axons at the microstructural level shows that alcohol alters the nodal domain in both male and female rats. 31 The nodes of Ranvier are the ion channel–rich gaps between myelin sheaths on the prefrontal axons, and reduced length-to-width nodal ratios were detected in male and female rats following adolescent binge drinking. 31 In males, the decrease in nodal ratio was due to an increase in nodal diameter after the exposure, whereas in females it was due to a decrease in the nodal length.…”

“… 31 The nodes of Ranvier are the ion channel–rich gaps between myelin sheaths on the prefrontal axons, and reduced length-to-width nodal ratios were detected in male and female rats following adolescent binge drinking. 31 In males, the decrease in nodal ratio was due to an increase in nodal diameter after the exposure, whereas in females it was due to a decrease in the nodal length. In both cases, these microstructural alterations have potential to negatively impact the speed and integrity of neural transmission, which is essential for effective communication within and between cortical and subcortical structures.…”

Chronic Exposure to Alcohol Inhibits New Myelin Generation in Adult Mouse Brain

“…In the present study, we applied 5 and 10% alcohol treatment for 3 weeks, representing a mild and moderate levels of alcohol intoxication, respectively (He et al, 2007;Alfonso-Loeches et al, 2012;Pascual et al, 2014;Vargas et al, 2014;Tavares et al, 2019).…”