Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain.

Ryan P Vetreno,Margaret Broadwater,Wen Liu,Linda P Spear,Fulton T Crews,Yael Abreu-Villaça

doi:10.1371/journal.pone.0113421

Ryan P Vetreno, Margaret Broadwater + Show 4 more

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https://doi.org/10.1371/journal.pone.0113421

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Abstract

During the adolescent transition from childhood to adulthood, notable maturational changes occur in brain neurotransmitter systems. The cholinergic system is composed of several distinct nuclei that exert neuromodulatory control over cognition, arousal, and reward. Binge drinking and alcohol abuse are common during this stage, which might alter the developmental trajectory of this system leading to long-term changes in adult neurobiology. In Experiment 1, adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) treatment led to persistent, global reductions of choline acetyltransferase (ChAT) expression. Administration of the Toll-like receptor 4 agonist lipopolysaccharide to young adult rats (P70) produced a reduction in ChAT+IR that mimicked AIE. To determine if the binge ethanol-induced ChAT decline was unique to the adolescent, Experiment 2 examined ChAT+IR in the basal forebrain following adolescent (P28–P48) and adult (P70–P90) binge ethanol exposure. Twenty-five days later, ChAT expression was reduced in adolescent, but not adult, binge ethanol-exposed animals. In Experiment 3, expression of ChAT and vesicular acetylcholine transporter expression was found to be significantly reduced in the alcoholic basal forebrain relative to moderate drinking controls. Together, these data suggest that adolescent binge ethanol decreases adult ChAT expression, possibly through neuroimmune mechanisms, which might impact adult cognition, arousal, or reward sensitivity.

Highlights

Adolescence is a neurodevelopmental period in humans and other mammalian species encompassing the transition from childhood to adulthood, and includes increased social interactions, interest in risky behavior, and ethanol consumption [1]
Choline acetyltransferase, which provides a measure of cholinergic cell populations [25], was assessed in all major cholinergic brain nuclei following adolescent binge ethanol exposure
We report here for the first time that protein expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are reduced in the postmortem human alcoholic basal forebrain in comparison to moderate drinking controls

Summary

Introduction

Adolescence is a neurodevelopmental period in humans and other mammalian species encompassing the transition from childhood to adulthood, and includes increased social interactions, interest in risky behavior (i.e., novelty- and sensation-seeking), and ethanol consumption [1]. The basal forebrain consists of the medial septum and vertical limb of the diagonal band (Ch1/2) that project to the hippocampus. Cholinergic neurons of the nucleus basalis magnocellularis (Ch4) provide major inputs to the entire neocortex and basolateral amygdala, consistent with involvement of the basal forebrain in cognition, executive function, and stress/anxiety states [4,5,6,7]. Cholinergic cells of the pedunculopontine (Ch5) and the laterodorsal tegmental nucleus (Ch6) project to the thalamus [7], and regulate cortical arousal and behavioral control [8]. The medial habenula (Ch7) projects to the interpeduncular nucleus [9], and plays a role in avoidance learning and behavioral control [10] as well as possibly contributing to habenular regulation of reward pathways [11]. Continued maturation of the brain cholinergic system during adolescence likely contributes to maturation of multiple brain functions

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