Immune control of sleep pressure via interferon-γ in mice

Sleep pressure reflects the brain's homeostatic need to sleep, but the mechanisms underlying its regulation remain poorly understood. In mice, a subset of cortical inhibitory neuronal nitric oxide synthase (nNOS) positive interneurons tunes the electroencephalographic slow wave activity in the delta band (<4 Hz), marker of sleep pressure. Here, we demonstrate that in mice the natural killer (NK) cells and innate lymphoid cells (ILC)1 depletion inhibits nNOS+ interneurons and EEG delta activity reducing the time spent in the non-rapid eye movement (NREM) sleep. The optogenetic re-activation of nNOS+ interneurons in the cingulate cortex of NK cell/ILC1-depleted mice rescues the EEG delta activity, confirming the link between innate immune cells-nNOS+ interneurons-sleep pressure. Finally, we demonstrated that meningeal NK/ILC1 cells produce IFN-γ in a circadian independent manner and that IFN-γ blockade in vivo mimics the effect of NK cell depletion in mice. These findings provide insights into the complex network involved in sleep regulation and further support the contribution of the innate immune system on sleep pressure.