Research ArticleNeuroscience

ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness

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Sci. Signal.  24 Jan 2017:
Vol. 10, Issue 463, eaai9219
DOI: 10.1126/scisignal.aai9219

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ERK preps the brain for sleep

Why do we feel more tired and tend to sleep longer and more deeply after a period of sleep deprivation or after a day that was full of physical or mental activity? Findings from Mikhail et al. using mice and cultured cortical neurons suggest that sleep deprivation or activity during the waking hours stimulates gene expression dependent in part on the kinase ERK. Signaling by the ERK pathway increased the duration of sleep and affected sleep patterns. Genetic deletion of ERK in cortical neurons or intracranial injection of an ERK inhibitor reduced the amount of sleep and extended the duration of wakefulness in mice. The findings support a previously reported link between sleep and ERK in flies to provide insight into the mechanisms regulating sleep in mammals.

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.

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