title: Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and Toll-like receptors in the adult prefrontal cortex.
abstract: Adolescence is a critical developmental stage of life during which the prefrontal cortex (PFC) matures, and binge drinking and alcohol abuse are common. Recent studies have found that ethanol increases neuroinflammation via upregulated high-mobility group box 1 (HMGB1) signaling through Toll-like receptors (TLRs). HMGB1/TLR 'danger signaling' induces multiple brain innate immune genes that could alter brain function. To determine whether adolescent binge drinking persistently increases innate immune gene expression in the PFC, rats (P25-P55) were exposed to adolescent intermittent ethanol (AIE [5.0 g/kg, 2-day on/2-day off schedule]). On P56, HMGB1/TLR danger signaling was assessed using immunohistochemistry (i.e., +immunoreactivity [+IR]). In a separate group of subjects, spatial and reversal learning on the Barnes maze was assessed in early adulthood (P64-P75), and HMGB1/TLR danger signaling was measured using immunohistochemistry for +IR and RT-PCR for mRNA in adulthood (P80). Immunohistochemical assessment at P56 and 24 days later at P80 revealed increased frontal cortical HMGB1, TLR4, and TLR3 in the AIE-treated rats. Adolescent intermittent ethanol treatment did not alter adult spatial learning on the Barnes maze, but did cause reversal learning deficits and increased perseverative behavior. Barnes maze deficits correlated with the expression of danger signal receptors in the PFC. Taken together, these findings provide evidence that adolescent binge drinking leads to persistent upregulation of innate immune danger signaling in the adult PFC that correlates with adult neurocognitive dysfunction.
authors.affiliation: The Bowles Center for Alcohol Studies, Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. rvetreno@email.unc.edu
authors.forename: R P
authors.initials: RP
authors.lastname: Vetreno
authors.forename: F T
authors.initials: FT
authors.lastname: Crews
mesh_terms: D000293:Adolescent; D000818:Animals; D063425:Binge Drinking / Q000235:genetics* / Q000378:metabolism*; D003072:Cognition Disorders / Q000139:chemically induced / Q000523:psychology; D005260:Female; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D018782:Maze Learning / Q000187:drug effects; D018613:Microscopy, Confocal; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012193:Reversal Learning / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000187:drug effects; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D024243:HMGB1 Protein; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors