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Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and toll-like receptors in the adult prefrontal cortex
Open accessAbstract
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.
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“They found that previous adolescent ethanol exposure did not impact acquisition of the Barnes maze but did disrupt reversal learning in adulthood, with alcohol exposed mice exhibiting longer latencies to find the new escape hole and spending a longer time in the previously learned hole location when compared to controls.”
From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Vetreno and Crews 2012
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“Although there is evidence for persistent neurological and cognitive deficits in HC function, it is important to note that certain aspects of HC-dependent learning and memory, such as spatial learning and memory, were not impacted following adolescent exposure (Coleman et al. 2011; Vetreno and Crews 2012) but were in adults (Cippitelli et al. 2010).”
From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Vetreno and Crews 2012
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Research works printed but not linked: 2
- Crews FT, Qin L, Sheedy D, Vetreno RP, Zou J (in press) HMGB1/TLR receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry.
- Johnston, 2009, Vol. 1
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Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence?
SPEAR, L. P. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.01.027 · Cited by 383
Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior
Crews, F. T., Vetreno, R. P., Broadwater, M., & Robinson, D. L. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.012138 · Cited by 356
Self-citationThe role of neuroimmune signaling in alcoholism
Crews, F. T., Lawrimore, C. J., Walter, T. J., & Coleman, L. G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.01.031 · Cited by 321
Self-citationMechanisms of neuroimmune gene induction in alcoholism
Crews, F. T., & Vetreno, R. P. (2016) · Psychopharmacology · doi:10.1007/s00213-015-3906-1 · Cited by 232
Self-citationNeuroimmune Function and the Consequences of Alcohol Exposure
Crews, F. T. (2015) · Alcohol research · doi:10.35946/arcr.v37.2.15 · Cited by 203
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Metadata
- Authors
- Vetreno, R. P., & Crews, F. T.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Vetreno, R.P.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 226
- Pages
- 475-488
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC3740555
- OpenAlex
- W2089714619
- Cited by
- 183
- References
- 66
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 8 · 2022: 16 · 2021: 23 · 2020: 14 · 2019: 14 · 2018: 9 · 2017: 20 · 2016: 15 · 2015: 15 · 2014: 11 · 2013: 8
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Center for Alcohol Studies
- National Institutes of Health (AA-11605, AA007573, AA019767)
- National Institute on Alcohol Abuse and Alcoholism (P50AA011605, AA 11605, U24AA020022, U01AA020023, AA020023, L40 AA021590, AA021040, AA 007573, F32AA021040, AA020022, AA020024, U24AA020024, U54AA019767, AA019767, P60AA011605, T32AA007573)
- Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- adolescent binge drinking, prefrontal cortex, HMGB1, danger signaling, TLR4, TLR3, neuroinflammation, innate immunity, spatial learning, perseveration, neurocognitive impairment, alcohol abuse
- MeSH terms
- Adolescent, Animals, Cognition Disorders, Female, Fluorescent Antibody Technique, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Reversal Learning, Rats, Wistar, Prefrontal Cortex, Microscopy, Confocal, Maze Learning, HMGB1 Protein, Toll-Like Receptors, Toll-Like Receptor 3, Toll-Like Receptor 4, Rats, Real-Time Polymerase Chain Reaction, Binge Drinking
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