Neuroimmune and epigenetic involvement in adolescent binge ethanol‐induced loss of basal forebrain cholinergic neurons: Restoration with voluntary exercise

Abstract

Binge drinking and alcohol abuse are common during adolescence and cause lasting pathology. Preclinical rodent studies using the adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P]25 to P55) model of human adolescent binge drinking report decreased basal forebrain cholinergic (ie, ChAT+) neurons that persist into adulthood (ie, P56-P220). Recent studies link AIE-induced neuroimmune activation to cholinergic pathology, but the underlying molecular mechanisms contributing to the persistent loss of basal forebrain ChAT+ neurons are unknown. We report here that the AIE-induced loss of cholinergic neuron markers (ie, ChAT, TrkA, and p75 NTR ), cholinergic neuron shrinkage, and increased expression of the neuroimmune marker pNF-κB p65 are restored by exercise exposure from P56 to P95 after AIE. Our data reveal that persistently reduced expression of cholinergic neuron markers following AIE is because of the loss of the cholinergic neuron phenotype most likely through an epigenetic mechanism involving DNA methylation and histone 3 lysine 9 dimethylation (H3K9me2). Adolescent intermittent ethanol caused a persistent increase in adult H3K9me2 and DNA methylation at promoter regions of Chat and H3K9me2 of Trka, which was restored by wheel running. Exercise also restored the AIE-induced reversal learning deficits on the Morris water maze.Together, these data suggest that AIE-induced adult neuroimmune signaling and cognitive deficits are linked to suppression of Chat and Trka gene expression through epigenetic mechanisms that can be restored by exercise. Exercise restoration of the persistent AIE-induced phenotypic loss of cholinergic neurons via epigenetic modifications is novel mechanism of neuroplasticity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

“…Thus, we postulate that moderate exercise may help reduce cravings and ultimately reduce alcohol intake of moderate consumers. In addition, moderate exercise has been demonstrated to ameliorate specific pathological neuronal consequences and improve cognitive deficits caused by alcohol consumption . Together, the results of these studies suggest that moderate exercise may be useful to cease or reverse negative neuronal consequences caused by moderate alcohol intake.…”

“…The long‐term consequences of repeated neuroinflammation and oxidative stress include a decline in cognitive function . In contrast, regular exercise has been shown to increase reaction time, nonspatial memory, object recognition, spatial learning and overall cognitive performance .…”

“…As mentioned above, exercise may be able to prevent and reverse a portion of the neuroinflammation and oxidative stress caused by alcohol consumption. Thus, there is an emerging body of work supporting the hypothesis that physical exercise may be able to repair cognitive deficits caused by heavy alcohol consumption . In several studies of adolescent and adult male Wistar and Long‐Evans rats (females not tested), those exposed to physical activity following binge‐alcohol exposure demonstrated improved cognitive function, motor activity and short‐term recognition memory .…”

“…The long-term consequences of repeated neuroinflammation and oxidative stress include a decline in cognitive function. 37,40,49,50 In contrast, regular exercise has been shown to increase reaction time, nonspatial memory, object recognition, spatial learning and overall cognitive performance. 43,[51][52][53][54] As mentioned above, exercise may be able to prevent and reverse a portion of the neuroinflammation and oxidative stress caused by alcohol consumption.…”

“…Thus, there is an emerging body of work supporting the hypothesis that physical exercise may be able to repair cognitive deficits caused by heavy alcohol consumption. 34,37,42,43,49 In several studies of adolescent and adult male Wistar and Long-Evans rats (females not tested), those exposed to physical activity following binge-alcohol exposure demonstrated improved cognitive function, motor activity and short-term recognition memory. 34,37,42,43,49 Again, there has been an imbalance in study across sexes in this body of literature, especially given the knowledge that females display greater susceptibility to acute and long-term memory alterations due to alcohol consumption.…”