title: ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness.
abstract: Wakefulness is accompanied by experience-dependent synaptic plasticity and an increase in activity-regulated gene transcription. Wake-induced genes are certainly markers of neuronal activity and may also directly regulate the duration of and need for sleep. We stimulated murine cortical cultures with the neuromodulatory signals that are known to control wakefulness in the brain and found that norepinephrine alone or a mixture of these neuromodulators induced activity-regulated gene transcription. Pharmacological inhibition of the various signaling pathways involved in the regulation of gene expression indicated that the extracellular signal-regulated kinase (ERK) pathway is the principal one mediating the effects of waking neuromodulators on gene expression. In mice, ERK phosphorylation in the cortex increased and decreased with wakefulness and sleep. Whole-body or cortical neuron-specific deletion of Erk1 or Erk2 significantly increased the duration of wakefulness in mice, and pharmacological inhibition of ERK phosphorylation decreased sleep duration and increased the duration of wakefulness bouts. Thus, this signaling pathway, which is highly conserved from Drosophila to mammals, is a key pathway that links waking experience-induced neuronal gene expression to sleep duration and quality.
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Cyril
authors.initials: C
authors.lastname: Mikhail
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Angélique
authors.initials: A
authors.lastname: Vaucher
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Jimenez
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland. mehdi.tafti@unil.ch.|Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Tafti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D000072233:Homer Scaffolding Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012890:Sleep / Q000235:genetics*; D012892:Sleep Deprivation; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness / Q000235:genetics*
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D014157:Transcription Factors; C092069:activity regulated cytoskeletal-associated protein; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3