Article

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: 3.36). 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.

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    • "For example, it has been demonstrated that the expression of select neurotransmitter receptor genes is decreased following alcohol exposure (Coleman et al., 2011), particularly in cholinergic, GABAergic, and peptide genes. Conversely, the expression of genes involved in intracellular signaling pathways in the extended amygdala and prefrontal cortex is increased (McBride et al., 2014; Vetreno and Crews, 2012). While these studies have produced promising results, the alteration of gene expression patterns within the peripheral blood following alcohol binging remains poorly characterized , even in the cases of genes that control gene expression (i.e., epigenetic genes). "

    No preview · Article · Sep 2015 · Alcohol and Alcoholism
    • "For example, it has been demonstrated that the expression of select neurotransmitter receptor genes is decreased following alcohol exposure (Coleman et al., 2011), particularly in cholinergic, GABAergic, and peptide genes. Conversely, the expression of genes involved in intracellular signaling pathways in the extended amygdala and prefrontal cortex is increased (McBride et al., 2014; Vetreno and Crews, 2012). While these studies have produced promising results, the alteration of gene expression patterns within the peripheral blood following alcohol binging remains poorly characterized , even in the cases of genes that control gene expression (i.e., epigenetic genes). "
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    ABSTRACT: Background Alcohol binge drinking is one of the most common patterns of excessive alcohol use and recent data would suggest that histone deacetylases (HDACs) gene expression profiling could be useful as a biomarker for psychiatric disorders.Methods This study aimed to characterize the gene expression patterns of Hdac 1–11 in samples of rat peripheral blood, liver, heart, prefrontal cortex, and amygdala following repeated binge alcohol consumption and to determine the parallelism of Hdac gene expression between rats and humans in peripheral blood. To accomplish this goal, we examined Hdac gene expression following 1, 4, or 8 alcohol binges (3 g/kg, orally) in the rat, in patients who were admitted to the hospital emergency department for acute alcohol intoxication, and in rats trained in daily operant alcohol self-administration.ResultsWe primarily found that acute alcohol binging reduced gene expression (Hdac1–10) in the peripheral blood of alcohol-naïve rats and that this effect was attenuated following repeated alcohol binges. There was also a reduction of Hdac gene expression in the liver (Hdac2,4,5), whereas there was increased expression in the heart (Hdac1,7,8) and amygdala (Hdac1,2,5). Additionally, increased blood alcohol concentrations were measured in rat blood at 1 to 4 hours following repeated alcohol binging, and the only group that developed hepatic steotosis (fatty liver) were those animals exposed to 8 alcohol binge events. Finally, both binge consumption of alcohol in humans and daily operant alcohol self-administration in rats increased Hdac gene expression in peripheral blood.Conclusions Our results suggest that increases in HDAC gene expression within the peripheral blood are associated with chronic alcohol consumption, whereas HDAC gene expression is reduced following initial exposure to alcohol.
    No preview · Article · Sep 2015 · Alcoholism Clinical and Experimental Research
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    • "Blood samples were collected from the tail on P38 and P54 and blood ethanol content (BECs) was analyzed using a GM7 analyzer (Analox, London, UK). Mean BEC levels (mean ± SD) on P38 were 168 (±47) mg/dl and at P54 were 178 (±66) mg/dl, which are consistent with the previous studies from our laboratory (Vetreno & Crews 2012). Following the conclusion of AIE treatment , subjects were housed in pairs (n = 2 per cage) and maintained on ad libitum access to food and water for the duration of the experiments. "
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    ABSTRACT: Adolescence is characterized by considerable brain maturation that coincides with the development of adult behavior. Binge drinking is common during adolescence and can have deleterious effects on brain maturation because of the heightened neuroplasticity of the adolescent brain. Using an animal model of adolescent intermittent ethanol [AIE; 5.0 g/kg, intragastric, 20 percent EtOH w/v; 2 days on/2 days off from postnatal day (P)25 to P55], we assessed the adult brain structural volumes and integrity on P80 and P220 using diffusion tensor imaging (DTI). While we did not observe a long-term effect of AIE on structural volumes, AIE did reduce axial diffusivity (AD) in the cerebellum, hippocampus and neocortex. Radial diffusivity (RD) was reduced in the hippocampus and neocortex of AIE-treated animals. Prior AIE treatment did not affect fractional anisotropy (FA), but did lead to long-term reductions of mean diffusivity (MD) in both the cerebellum and corpus callosum. AIE resulted in increased anxiety-like behavior and diminished object recognition memory, the latter of which was positively correlated with DTI measures. Across aging, whole brain volumes increased, as did volumes of the corpus callosum and neocortex. This was accompanied by age-associated AD reductions in the cerebellum and neocortex as well as RD and MD reductions in the cerebellum. Further, we found that FA increased in both the cerebellum and corpus callosum as rats aged from P80 to P220. Thus, both age and AIE treatment caused long-term changes to brain structural integrity that could contribute to cognitive dysfunction. © 2015 Society for the Study of Addiction.
    Full-text · Article · Feb 2015 · Addiction Biology
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