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

Abstract

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.

Alcohol Intoxication and Cognition: Implications on Mechanisms and Therapeutic Strategies

“…This task is sensitive to lesions in the hippocampus, anterior thalamus and cingulate cortex (Bussey et al, 2000;Warburton et al, 2000). In our study, alcohol exposure showed a significant decrease in OPM between pre-and post-alcohol exposure indicating impaired spatial memory (Jacob et al, 2019). Alcohol exposure also displayed lower exploration of the center of the field in OF task as compared to pre-alcohol (Jacob et al, 2019).…”

“…In our study, alcohol exposure showed a significant decrease in OPM between pre-and post-alcohol exposure indicating impaired spatial memory (Jacob et al, 2019). Alcohol exposure also displayed lower exploration of the center of the field in OF task as compared to pre-alcohol (Jacob et al, 2019). In the OF task, the exploration of the center as opposed to periphery indicate increased anxiety and familiarization to the environment.…”

“…We and others have shown that acute alcohol caused reduction in brain activities in the cortical regions and subcortical regions including the temporal lobe (Volkow et al, 1990(Volkow et al, , 2008Jacob et al, 2019). The medial temporal lobe consists of the hippocampus and the adjacent entorhinal and perirhinal cortex which are prominent regions required for cognition, including learning and memory (Squire et al, 2004).…”

“…Recently, we conducted a study using a mouse model of binge alcohol exposure and measured brain glucose metabolism and cognitive performance in the same cohort of mice (Jacob et al, 2019). Our model consisted mice, each receiving a continuous intravenous administration of a bolus dose of alcohol (1.5 g/kg) referred to a bolus infusion for over a 20 min period.…”

“…The BAC in this model reached to 37-38 mM (0.17%) 1 h after the bolus infusion. Using this mouse model of alcohol, we examined the effect of alcohol in brain glucose metabolism and cognitive performance using 18 FDG-PET and behavioral tasks, respectively (Jacob et al, 2019). First, mice were subjected to behavior tasks and a microPET scan to assess basal behavior and brain glucose metabolism, respectively.…”