Abstract
BackgroundAlcohol abuse affects the brain regions responsible for memory, coordination and emotional processing. Binge alcohol drinking has shown reductions in brain activity, but the molecular targets have not been completely elucidated. We hypothesized that brain cells respond to excessive alcohol by releasing a novel inflammatory mediator, called cold inducible RNA-binding protein (CIRP), which is critical for the decreased brain metabolic activity and impaired cognition.MethodsMale wild type (WT) mice and mice deficient in CIRP (CIRP−/−) were studied before and after exposure to binge alcohol level by assessment of relative brain glucose metabolism with fluorodeoxyglucose (18FDG) and positron emission tomography (PET). Mice were also examined for object-place memory (OPM) and open field (OF) tasks.ResultsStatistical Parametric Analysis (SPM) of 18FDG-PET uptake revealed marked decreases in relative glucose metabolism in distinct brain regions of WT mice after binge alcohol. Regional analysis (post hoc) revealed that while activity in the temporal (secondary visual) and limbic (entorhinal/perirhinal) cortices was decreased in WT mice, relative glucose metabolic activity was less suppressed in the CIRP−/− mice. Group and condition interaction analysis revealed differing responses in relative glucose metabolism (decrease in WT mice but increase in CIRP−/− mice) after alcohol in brain regions including the hippocampus and the cortical amygdala where the percent changes in metabolic activity correlated with changes in object discrimination performance. Behaviorally, alcohol-treated WT mice were impaired in exploring a repositioned object in the OPM task, and were more anxious in the OF task, whereas CIRP−/− mice were not impaired in these tasks.ConclusionCIRP released from brain cells could be responsible for regional brain metabolic hypoactivity leading to cognitive impairment under binge alcohol conditions.
Highlights
Binge drinking is a popular mode of alcohol intake in young adults and the worldwide prevalence of such occurrence is about 16% (Global status report on alcohol and health 2018, Geneva: World Health Organization, https://www.who.int/substance_abuse/ publications/global_alcohol_report/en/)
cold inducible RNA-binding protein (CIRP) deficiency attenuated the decrease in brain metabolic activity observed in wild type (WT) mice after binge alcohol We observed, using the region-of-interest analysis, that the percent (%) changes of the globally normalized metabolic values were decreased to a smaller degree in CIRP−/− mice compared to WT mice
Regional metabolic activity is significantly correlated with spatial cognition after binge alcohol exposure In a correlation analysis where the data were combined between WT and CIRP−/− mice (n = 17), there was a strong correlation between the changes in discrimination ratio and the percent changes in metabolic activity the fimbria of the hippocampus (r = 0.73, P < 0.001) and in the Posteriomedial cortical amygdaloid area (PMCoAA) (r = 0.53, P = 0.03) (Fig. 5)
Summary
Binge drinking is a popular mode of alcohol intake in young adults and the worldwide prevalence of such occurrence is about 16% (Global status report on alcohol and health 2018, Geneva: World Health Organization, https://www.who.int/substance_abuse/ publications/global_alcohol_report/en/). Binge alcohol drinking has shown reductions in brain activity, but the molecular targets have not been completely elucidated. Methods: Male wild type (WT) mice and mice deficient in CIRP (CIRP−/−) were studied before and after exposure to binge alcohol level by assessment of relative brain glucose metabolism with fluorodeoxyglucose (18FDG) and positron emission tomography (PET). Results: Statistical Parametric Analysis (SPM) of 18FDG-PET uptake revealed marked decreases in relative glucose metabolism in distinct brain regions of WT mice after binge alcohol. Group and condition interaction analysis revealed differing responses in relative glucose metabolism (decrease in WT mice but increase in CIRP−/− mice) after alcohol in brain regions including the hippocampus and the cortical amygdala where the percent changes in metabolic activity correlated with changes in object discrimination performance. Alcohol-treated WT mice were impaired in exploring a repositioned object in the OPM task, and were more anxious in the OF task, whereas CIRP−/− mice were not impaired in these tasks
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