Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and toll-like receptors in the adult prefrontal cortex

The Bowles Center for Alcohol Studies, Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: .
Neuroscience (Impact Factor: 3.33). 09/2012; 226. DOI: 10.1016/j.neuroscience.2012.08.046
Source: PubMed

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 [5.0g/kg, e.g., 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 24days 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.

Download full-text


Available from: Ryan P Vetreno, Jul 27, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Molecular and behavioral studies corroborate a pivotal role for the innate immune system in mediating the acute and chronic effects of alcohol and support a neuroimmune hypothesis of alcohol addiction. Changes in expression of neuroimmune genes and microglial transcripts occur in postmortem brain from alcoholics and animals exposed to alcohol, and null mutant animals lacking certain innate immune genes show decreased alcohol-mediated responses. Many of the differentially expressed genes are part of the toll like receptor (TLR) signaling pathway and culminate in an increased expression of pro-inflammatory immune genes. Compounds known to inhibit inflammation, microglial activation, and neuroimmune gene expression have shown promising results in reducing alcohol-mediated behaviors in animal models, indicating that neuroimmune signaling pathways offer unexplored targets in the treatment of alcohol abuse.
    Current opinion in neurobiology 02/2013; 23(4). DOI:10.1016/j.conb.2013.01.024 · 6.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Up to two thirds of adolescents consume alcohol and about a quarter engage in abusive behavior at some point. Many users begin alcohol use at young ages, and binge drinking is a dominant pattern for a proportion of youth. Because neurogenesis is inhibited by ethanol, consequences of adolescent alcohol abuse include changes in brain development and impairment of neurocognitive performance. A variety of mental and psychosocial problems are also often witnessed in alcohol abusing youth. Apart from the influence exerted by genetic and psychosocial factors, the chance of developing problematic alcohol consumption is increased by consumption in a binge drinking manner and by first contact with alcohol at a young age. Discrimination of alcohol consumption within the frames of normal adolescent behavior from problematic use is still a challenging issue. Different prevention programs provide treatment either directly to the adolescent, in the context of the school, or within the frame of the adolescent's family. Although some of these efforts have been shown to be effective in reducing alcohol misuse in youth, hardly any intervention reveals satisfactory outcomes in a long-term prospect. Successful prevention strategies would need to comprise treatment of current neuropsychological impairment as well as of comorbid mental health problems and concurrent other substance misuse.
    Neuropsychiatrie: Klinik, Diagnostik, Therapie und Rehabilitation: Organ der Gesellschaft Österreichischer Nervenärzte und Psychiater 07/2013; 27(4). DOI:10.1007/s40211-013-0066-6 · 1.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adolescence is characterized behaviorally by increased impulsivity and risk-taking that declines in parallel with maturation of the prefrontal cortex and executive function. In the brain, the receptor for advanced glycation end products (RAGE) is critically involved in neurodevelopment and neuropathology. In humans, the risk of alcoholism is greatly increased in those who begin drinking between 13 and 15 years of age, and adolescents binge drink more than any other age group. We have previously found that alcoholism is associated with increased expression of neuroimmune genes. This manuscript tested the hypothesis that adolescent binge drinking upregulates RAGE and Toll-like receptor (TLR) 4 as well as their endogenous agonist, high-mobility group box 1 (HMGB1). Immunohistochemistry, Western blot, and mRNA analyses found that RAGE expression was increased in the human post-mortem alcoholic orbitofrontal cortex (OFC). Further, an earlier age of drinking onset correlated with increased expression of RAGE, TLR4, and HMGB1. To determine if alcohol contributed to these changes, we used an adolescent binge ethanol model in rats (5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) and assessed neuroimmune gene expression. We found an age-associated decline of RAGE expression from late adolescence (P56) to young adulthood (P80). Adolescent intermittent ethanol exposure did not alter RAGE expression at P56, but increased RAGE in the young adult PFC (P80). Adolescent intermittent ethanol exposure also increased TLR4 and HMGB1 expression at P56 that persisted into young adulthood (P80). Assessment of young adult frontal cortex mRNA (RT-PCR) found increased expression of proinflammatory cytokines, oxidases, and neuroimmune agonists at P80, 25 days after ethanol treatment. Together, these human and animal data support the hypothesis that an early age of drinking onset upregulates RAGE/TLR4-HMGB1 and other neuroimmune genes that persist into young adulthood and could contribute to risk of alcoholism or other brain diseases associated with neuroinflammation.
    Neurobiology of Disease 07/2013; 59. DOI:10.1016/j.nbd.2013.07.002 · 5.20 Impact Factor
Show more