Enhancing cortical electrophysiological signatures of sleep overrides ER stress responses in sleep-deprived mice

Sleep deprivation (SD) triggers characteristic changes in the cortical electroencephalogram (EEG) during waking and sleep, as well as upregulating molecular signatures of neuronal activity, synaptic plasticity, and endoplasmic reticulum (ER) stress. This includes the induction of the unfolded protein response (UPR), the primary marker and adaptive mechanism of ER stress. Yet how cortical neuronal activity during SD contributes to the induction of these molecular signatures remains unknown. Here we investigate whether manipulating cortical activity during SD with a physiological stimulation paradigm (flickering light stimulation, FLS) affects the induction of the UPR. As expected, SD alone upregulated activity-dependent and UPR-related genes in cortex and led to increased EEG slow-wave activity (SWA) during subsequent NREM sleep, an electrophysiological signature of sleep need. Delivering FLS during SD, however, prevented the upregulation of activity- and UPR-related genes while inducing an additional increase in SWA during subsequent sleep. Further analysis of neuronal firing revealed that FLS induced brief neuronal silent (OFF) periods in awake animals during stimulation, thereby shifting cortical activity towards a brain state resembling sleep. These findings suggest that physiological manipulation of cortical activity during waking is sufficient to dissociate molecular signatures of ER stress from electrophysiological markers of sleep pressure. We propose that global sleep wake history and cortical network dynamics differentially regulate activity-dependent transcription and the accumulation of sleep pressure.