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Conscious perception is greatly diminished during sleep, but the underlying circuit mechanism is poorly understood. We show that cortical ignition—a brain process shown to be associated with conscious awareness in humans and non-human primates—is strongly suppressed during non-rapid-eye-movement (NREM) sleep in mice due to reduced cholinergic modulation and rapid inhibition of cortical responses. Brain-wide functional ultrasound imaging and cell-type-specific calcium imaging combined with optogenetics showed that activity propagation from visual to frontal cortex is markedly reduced during NREM sleep due to strong inhibition of frontal pyramidal neurons. Chemogenetic activation and inactivation of basal forebrain cholinergic neurons powerfully increased and decreased visual-to-frontal activity propagation, respectively. Furthermore, although multiple subtypes of dendrite-targeting GABAergic interneurons in the frontal cortex are more active during wakefulness, soma-targeting parvalbumin-expressing interneurons are more active during sleep. Chemogenetic manipulation of parvalbumin interneurons showed that sleep/wake-dependent cortical ignition is strongly modulated by perisomatic inhibition of pyramidal neurons. [Display omitted] • Visual-to-frontal cortex activity propagation is strongly reduced during NREM sleep • Responses of frontal pyramidal neurons are strongly inhibited during NREM sleep • Basal forebrain cholinergic neurons powerfully modulate frontal cortical ignition • Increased perisomatic inhibition during NREM sleep suppresses cortical ignition Investigation into the circuit mechanisms that diminish awareness during sleep shows that frontal cortical ignition is suppressed during NREM sleep due to reduced cholinergic modulation and a shift from dendritic to perisomatic inhibition of frontal cortical pyramidal neurons. [ABSTRACT FROM AUTHOR]

Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D 2 (PGD 2) in the brain, and we found that elevated PGD 2 efflux across the blood-brain-barrier—mediated by ATP-binding cassette subfamily C4 transporter—induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD 2 /DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD 2 in the central nervous system drive profound pathological consequences in the peripheral immune system. [Display omitted] • A highly efficient paradigm is introduced for depriving mice of sleep • PGD 2 efflux across the BBB is enhanced by sleep deprivation • Sleep deprivation triggers increases in both cytokines and circulating neutrophils • The sleep-deprived brain affects the peripheral immune system via the PGD 2 /DP1 axis Enhanced efflux of PGD 2 across the BBB during prolonged sleep deprivation induces a cytokine-storm-like syndrome via the PGD 2 /DP1 axis. Sleep deprivation in mice that involves disruption of REMS and NREMS leads to lethality due to brain prostaglandin D 2 -mediated cytokine-storm-like systemic inflammation. [ABSTRACT FROM AUTHOR]