A tripartite flip-flop sleep circuit switches sleep states

Inhibitory sleep-active neurons depolarize at sleep onset to shut down the activity of wakefulness circuits. Wake-active arousal neurons in turn suppress inhibitory sleep-active neurons, thus forming a bipartite flip-flop switch. However, how sleep states are switched is unclear because neural circuits that directly depolarize inhibitory sleep-active neurons are not understood. Using optogenetics, we solved the presynaptic circuit for depolarization of the sleep-active RIS neuron in Surprisingly, we found that the PVC forward command interneuron, which is known to control wake behavior, is a major activator of RIS. The PVCs are inhibited by reverse command interneurons, which are stimulated by arousing cues. This suggests a model for sleep switch operation in which declining arousal increases activation of PVC, thus triggering activation of RIS. Depolarization of RIS in turn promotes the activation of PVC, thus forming a positive feedback loop for all-or-none sleep induction. The flip-flop sleep switch in thus is tripartite and requires excitatory sleep-promoting neurons activated by wakefulness that act as an amplifier that translates reduced arousal into the depolarization of an inhibitory sleep-active neuron. A tripartite flip-flop switch likely also underlies sleep state switching in other animals including in mammals.