0155 Direct Electrical Stimulation of the Lateral Hypothalamus Consolidates Wake and Ameliorates Cataplexy in a Mouse Model of Narcolepsy Type 1. (27th April 2018)

• Record Type: Journal Article
• Authors: Rogers, A; Aiani, L; Pedersen, N; Willie, J
• Is Part Of: Sleep. Volume 41(2018)Supplement 1
• Page Start: A60
• Page End: A60
• Publication Date: 2018-04-27
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsy061.154
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Narcolepsy type 1 (narcolepsy with cataplexy) is caused by a loss of orexin/hypocretin neurotransmitter signaling and is characterized by sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS), and cataplexy, an abrupt loss of muscle tone triggered by strong emotions. Medical management is incompletely effective, motivating our search for alternative approaches. We tested whether direct electrical stimulation (analogous to clinical deep brain stimulation) of medial prefrontal cortex (mPFC, emotion-processing cortex) or lateral hypothalamus (LH, an arousal center) would provide benefit in a validated mouse model of narcolepsy type 1. Methods: We implanted 6 orexin-ataxin3 transgenic mice with nuchal EMG electrodes and surface frontal-parietal EEG electrodes for recording. Stereotactic bipolar simulation electrodes in LH (n=3) and mPFC (n=3) were also implanted. We collected EEG/EMG and behavioral data in freely behaving mice using a standard acquisition system (Pinnacle Technologies, Inc.) and analyzed recordings with Spike2 software (Cambridge Electronic Design, Ltd). Mice were recorded at baseline for 24 hours following recovery and tether habituation. After initial threshold stimulation testing to assess tolerability, mice then subjected to 3 hours of continuous electrical stimulation (LH: 15 Hz, 2-3V, and mPFC: 200 Hz bursts [2/s], 2-3V) during the active phase (lights off). Video/EEG/EMG were analyzed in 10-second epochs using standard criteria for REMS, non-REMS, wake, and cataplexy. Stimulation locations were verified histologically post-mortem. Results: Continuous stimulation of the LH consolidated wakefulness, increasing time spent in wake by 15–27%. Stimulation also decreased cataplexy frequency, thus reducing time spent in cataplexy by 86–100%. By comparison, mPFC stimulation produced no consistent behavioral change in any animal. No seizures were observed and behaviors such as feeding, drinking, and locomotor activity were grossly normal across stimulation conditions in both groups. Conclusion: This preliminary study suggests specificity and effectiveness of LH stimulation for narcolepsy, although further exploration of stimulation parameters, additional targets, and longer-term effects is required. Our findings constitute the first evidence that deep brain stimulation could provide an innovative therapy for narcolepsy type 1. Support (If Any): SRSF.