Genomewide effects of regular caffeine intake on hippocampal metabolism and learning-dependent transcription [ChIP-Seq]

Caffeine is the most widely consumed psychoactive substance worldwide. Strikingly, molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal-omics techniques. Our results revealed that caffeine exerts concerted pleiotropic effects in the hippocampus, at the epigenomic, proteomic and metabolomic levels, aimed at lowering metabolic-related processes while re-setting learning-associated transcriptome associated with neuronal activity. These processes involve BDNF, CREB and adenosine A2A receptors-related mechanisms. Altogether, these findings suggest that regular intake of caffeine improves the signal-to-noise ratio during information encoding in learning and bolsters the salience of information encoding in brain circuits. Overall design: Two-three month-old mice were randomly assigned to the two following experimental groups: water (control group) and caffeine. The caffeine solution was kept in dark bottles thus protected from light and changed weekly. Treatment started at eight to nine weeks of age and lasted for two weeks. The chronic caffeine treatment in mice has been set in order to mimic the usual dose range of caffeine consumption in Humans. The selected caffeine dose of 0.3 g/L p.o., administered through drinking water at 0.3 g/L, has been previously shown to provide a significant benefit in neurodegenerative contexts (Arendash et al., 2006; Arendash et al., 2009; Laurent et al., 2014).