Sleep and cardiovascular phenotype in middle-aged hypocretin-deficient narcoleptic mice

Narcolepsy with cataplexy (NC) is a lifelong disorder caused by loss of hypothalamic hypocretin/orexin (HCRT) neurones, often starting in childhood. NC patients show altered control of heart rate (HR) and a normotensive non-dipper blood pressure (BP) profile, but the natural history and prognostic significance of these alterations remain unclear. Similar alterations have been observed in HCRT-ataxin-3 transgenic (TG) NC mice lacking HCRT neurones, but studies have been limited to young adult individuals <4 months of age. Here we evaluated long-term effects of NC on derangements in the wake-sleep state and cardiovascular control by studying middle-aged TG. We chronically instrumented TG and wild-type mice aged 10-11 months with electrodes for sleep scoring and a telemetric transducer for BP and HR measurements. We then recorded mice in freely behaving conditions. TG showed a NC phenotype including fragmentation of wakefulness, reduced latency to rapid eye movement sleep (REMS) and cataplexy-like events. TG also showed blunted BP decline on entering non-rapid eye movement sleep (NREMS), enhanced BP increase on passing to REMS, increased HR, and blunted changes in HR upon arousal and awakening from NREMS. Histological and ultrastructural analysis of cardiovascular and renal tissue did not reveal evidence of subclinical hypertensive organ damage. These data indicate that HCRT neurone loss in TG causes alterations in wake-sleep behaviour and cardiovascular control that are not peculiar to the beginning of the disease but are maintained at least up to middle age. These alterations are similar to those in adult NC patients, but do not produce early subclinical damage to the heart and kidneys.