Extracellular cold inducible RNA-binding protein mediates binge alcohol-induced brain hypoactivity and impaired cognition in mice

Background: Alcohol 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. 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 ((18)FDG) and positron emission tomography (PET). Mice were also examined for object-place memory (OPM) and open field (OF) tasks. Results: Statistical Parametric Analysis (SPM) of (18)FDG-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. Conclusion: CIRP released from brain cells could be responsible for regional brain metabolic hypoactivity leading to cognitive impairment under binge alcohol conditions.