Induction of active (REM) sleep and motor inhibition by hypocretin in the nucleus pontis oralis of the cat

Hypocretin (orexin)-containing neurons in the hypothalamus, which have been implicated in the pathology of narcolepsy, project to nuclei in the brain stem reticular formation that are involved in the control of the behavioral states of sleep and wakefulness. Among these nuclei is the nucleus pontis oralis (NPO). Consequently, the present study was undertaken to determine if the hypocretinergic system provides regulatory input to neurons in the NPO with respect to the generation of the states of sleep and wakefulness. Accordingly, polygraphic recordings and behavioral observations were obtained before and after hypocretin-1 and -2 were microinjected into the NPO in chronic, unanesthetized cats. Microinjections of either hypocretin-1 or -2 elicited, with a short latency, a state of active [rapid eye movement (REM)] sleep that appeared identical to naturally occurring active sleep. The percentage of time spent in active sleep was significantly increased. Dissociated states, which are characterized by the presence of muscle atonia without one or more of the electrophysiological correlates of active sleep, also arose following the injection. The effect of juxtacellular application of hypocretin-1 on the electrical activity of intracellularly recorded NPO neurons was then examined in the anesthetized cat. In this preparation, the application of hypocretin-1 resulted in the depolarization of NPO neurons, an increase in the frequency of their discharge and an increase in their excitability. These latter data represent the first description of the in vivo action of hypocretin on intracellularly recorded neuronal activity and provide evidence that the active sleep-inducing effects of hypocretin are due to a direct excitatory action on NPO neurons. Therefore we suggest that hypocretinergic processes in the NPO may play a role in the generation of active sleep, particularly muscle atonia and therefore are likely to be involved in the pathology of narcolepsy.