Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription
Isabel Paiva, … , Anne-Laurence Boutillier, David Blum
Isabel Paiva, … , Anne-Laurence Boutillier, David Blum
Published May 10, 2022
Citation Information: J Clin Invest. 2022;132(12):e149371. https://doi.org/10.1172/JCI149371.
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Research Article Neuroscience

Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription

Abstract

Caffeine is the most widely consumed psychoactive substance in the world. Strikingly, the 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 chronic caffeine exerts concerted pleiotropic effects in the hippocampus at the epigenomic, proteomic, and metabolomic levels. Caffeine lowered metabolism-related processes (e.g., at the level of metabolomics and gene expression) in bulk tissue, while it induced neuron-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through fine-tuning of metabolic genes, while boosting the salience of information processing during learning in neuronal circuits.

Authors

Isabel Paiva, Lucrezia Cellai, Céline Meriaux, Lauranne Poncelet, Ouada Nebie, Jean-Michel Saliou, Anne-Sophie Lacoste, Anthony Papegaey, Hervé Drobecq, Stéphanie Le Gras, Marion Schneider, Enas M. Malik, Christa E. Müller, Emilie Faivre, Kevin Carvalho, Victoria Gomez-Murcia, Didier Vieau, Bryan Thiroux, Sabiha Eddarkaoui, Thibaud Lebouvier, Estelle Schueller, Laura Tzeplaeff, Iris Grgurina, Jonathan Seguin, Jonathan Stauber, Luisa V. Lopes, Luc Buée, Valérie Buée-Scherrer, Rodrigo A. Cunha, Rima Ait-Belkacem, Nicolas Sergeant, Jean-Sébastien Annicotte, Anne-Laurence Boutillier, David Blum

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Figure 1

Hippocampal epigenomic alterations associated with chronic caffeine consumption.

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Hippocampal epigenomic alterations associated with chronic caffeine cons...
(A) Volcano plot showing the differentially enriched genomic regions of H3K9/14ac (ChIP-Seq) upon chronic caffeine treatment (778 decreased and 3 increased peaks, FDR < 1 × 10–5). (B) GREAT analysis showing the most-enriched biological processes associated with the H3K9/14ac-decreased peaks in caffeine-treated mice. Blue arrows indicate metabolic process– and translation-related terms. (C) Volcano plot representing the differentially regulated regions of H3K27ac upon chronic caffeine treatment (2105 decreased and 4 increased peaks, with FDR < 1 × 10–5). (D) GREAT analysis representing the most common biological processes associated with the H3K27ac-decreased peaks in the caffeine group. Regulation of metabolic processes is indicated by the blue arrow. (E) KEGG pathway analyses of depleted regions of both histone marks. Dashed gray line indicates adjusted P < 0.05. Yellow and pink arrows correspond to highlighted pathways in F. (F) Functional protein-protein network analysis (STRING) representation of insulin- and glucagon-related genes found to be decreased in both histone acetylation marks. (G) A representation of genomic regions using Integrative Genomics Viewer (IGV) of the metabolic genes Irs1 and Gsk3b, showing significant (FDR<10-5) decreases in H3K27ac and H3K9/14ac after caffeine treatment. Two biological replicates per histone mark were used for ChIP-Seq experiments.