Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure. (17th February 2023)

• Record Type: Journal Article
• Authors: Macht, Victoria; Vetreno, Ryan; Elchert, Natalie; Fisher, Rachael; Crews, Fulton
• Is Part Of: Alcoholism. Volume 47:Number 3(2023)
• Page Start: 470
• Page End: 485
• Publication Date: 2023-02-17
• Subjects: acetylcholine -- alcohol -- cognitive flexibility -- doublecortin -- neuroinflammation; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.15019
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract: Background: Adolescent intermittent ethanol (AIE) exposure causes long‐term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE‐induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits. Methods: Male and female rats underwent AIE (5.0 g/kg/day ethanol or water, i.g., 2 day‐on/2 day‐off from postnatal day (PND) 25–54), followed by a 2‐week regimen of the anti‐inflammatory compound indomethacin (4.0 g/kg/day, PND 56–69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning. Results: AIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high‐mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase‐2 (COX‐2 + IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and co‐labeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE‐induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats. Conclusions: These data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2) anti‐inflammatory indomethacin treatment following AIE that restores these persistent molecular pathologies also restores spatial reversal learning deficits. Abstract : Adolescent intermittent ethanol (AIE) exposure impairs the adult cholinergic septohippocampal circuit and reduces hippocampal neurogenesis in both sexes. AIE also causes long‐term increases in hippocampal proinflammatory signaling in association with impaired reversal learning. Anti‐inflammatory interventions with indomethacin restore the septohippocampal cholinergic circuit, rescuing neurogenesis, and restoring the hippocampal environmental milieu, resulting in restoration in reversal learning deficits after AIE in both sexes. This highlights neuroinflammation as a molecular mediator of behavioral deficits after AIE in both sexes.