LAUSR

BACKGROUND Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions. OBJECTIVE We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration. METHODS Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon (1) behavior, using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and (2) neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos. RESULTS Brief 10-second stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-hour stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 minutes of DBS revealed dose-responsive neural activation within wake-active nuclei of the hypothalamus, thalamus, and ventral midbrain. CONCLUSION Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.