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.

Molecular Mechanisms of REM Sleep

“…Phosphorylation was indicated to play a role also in Process S, as the loss of calcium/CaMKII gene resulted in significant reduction of sleep (Tatsuki et al, 2016). This finding is further supported by the observation that the wakefulness induced phosphorylation in the extracellular signal-regulated kinase (ERK) proteins, which are upstream of a group of genes expressed in activity-dependent manner and involved in sleep regulation (Mikhail et al, 2017). Moreover, the following phosphoproteomics studies revealed a number of genes in the intracellular signaling pathways change their states of phosphorylation along with the sleep/wake cycles (Diering et al, 2017;Wang et al, 2018;Bruning et al, 2019).…”

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

“…Conversely, large decreases in MAPK phosphorylation occur during SWA induced by sedative or anesthetic agents and during the homeostatic regulation of waking SWA (Kohtala et al, 2016(Kohtala et al, , 2019b. Intriguingly, the MAPK pathway has been shown to regulate sleep duration through activity-induced gene expression during wakefulness, with p44/42-MAPK deletion or inhibition significantly increasing the duration of wakefulness in mice (Mikhail et al, 2017). Though the function of this phenomenon remains almost completely unstudied, ENCORE-D suggests that the period dominated by waking SWA in response to rapid-acting antidepressants represents a physiologically meaningful step for the subacute consolidation of activity-induced synaptic changes, involving alterations in both protein synthesis and energy metabolism, resembling deep or local sleep.…”

Sleep loss drives brain region- and cell type-specific alterations in ribosome-associated transcripts involved in synaptic plasticity and cellular timekeeping

“…20-500 ng of mRNA was used to synthesize cDNA using iScript's cDNA Synthesis Kit (Bio-Rad), cDNA diluted 1:10 in RNAse-free H 2 O, and measured using a CFX96 Real-Time System. Primers were designed for these studies, with the exception of Homer1a, for which sequences were established in a prior study (Mikhail et al, 2017). Primer specificity was confirmed using NIH Primer Blast (see Table S1 for primer sequences).…”