GABA neurons in the sublaterodorsal tegmental (SLD) nucleus suppress wakefulness in wild-type and narcoleptic mice

The sleep-wake cycle is generated by competing neural circuits that control the oscillation between wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. While the sublaterodorsal tegmental nucleus (SLD) is recognized for its role in REM sleep generation, the functional contribution of its GABAergic neurons (SLD ^GABA ) to sleep-wake regulation remains poorly understood. Here, we found that SLD ^GABA neurons function as a suppressor of wakefulness in both wild-type and narcoleptic mice. Optogenetic silencing of SLD ^GABA neurons rapidly induced robust wakefulness, while enhancing cortical and motor activity. Conversely, optogenetic activation of these neurons suppressed wakefulness and promoted NREM sleep. We found that SLD ^GABA neurons project extensively to wake-promoting brain regions, providing an anatomical basis for their wake-suppressing effects. Importantly, we discovered that SLD ^GABA neurons play a pathological role in narcolepsy: their activation in orexin-deficient mice triggered characteristic sleep attacks—rapid intrusions of NREM sleep during active wakefulness— while silencing these neurons rescued animals from both sleep attacks and cataplexy. Collectively, these findings establish SLD ^GABA neurons as a key regulator of arousal state transitions and identify them as a novel therapeutic target for the treatment of narcolepsy.