Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation

Abstract

AbstractNarcolepsy is characterized by increased REM sleep propensity and cataplexy. Although narcolepsy is caused by the selective loss or dysfunction of hypocretin (Hcrt) neurons within the lateral hypothalamus (LH), mechanisms underlying REM sleep propensity and cataplexy remain to be elucidated. We have recently shown that wild type (WT) mice increase REM sleep expression when exposed to thermoneutral ambient temperature (Ta) warming during the light (inactive) phase. We hypothesized that the loss of Hcrt may lead to exaggerated responses with respect to increased REM sleep and cataplexy during Ta warming. To test this hypothesis, Hcrt-KO mice were implanted for chronic sleep recordings and housed in a temperature-controlled cabinet. Sleep-wake expression and both spontaneous cataplexy and food-elicited cataplexy were evaluated at constant Ta and during a Ta manipulation protocol. Here we show several unexpected findings. First, Hcrt-KO mice show opposite circadian patterns with respect to REM sleep responsiveness to thermoneutral Ta warming compared to WT mice. As previous demonstrated, WT mice increased REM sleep when Ta warming is presented during the inactive (light) phase, whereas Hcrt-KO showed a significant decrease in REM sleep expression. In contrast, Hcrt-KO mice increased REM sleep expression upon exposure to Ta warming when presented during the active (dark) phase, a circadian time when WT mice showed no significant changes in REM sleep as a function of Ta. Second, we found that REM sleep and cataplexy can be dissociated through Ta manipulation. Specifically, although Ta warming significantly increased REM sleep expression in Hcrt-KO mice during the active phase, cataplexy bout number and total cataplexy duration significantly decreased. In contrast, cataplexy expression was favoured during Ta cooling when REM sleep expression significantly decreased. Finally, video actigraphy and sleep-wake recordings in Hcrt-KO mice demonstrated that Ta manipulation did not significantly alter waking motor activity patterns or waking or NREM sleep durations. These data suggest that neural circuits gating REM sleep and cataplexy expression can be dissociated with Ta manipulation.Statement of SignificanceCataplexy and the loss of muscle tone has historically been viewed as a component of REM sleep that inappropriately intrudes into wakefulness. In addition to fragmented sleep, the intrusion of REM-like events into wakefulness has led to the hypothesis that narcolepsy represents a dysregulation of boundary state control. We show that REM sleep and cataplexy can be dissociated during the dark (active) phase through Ta manipulation. Such dissociation may provide clues regarding the cause of boundary state instability in Hcrt-KO mice, as well as provide a new method to interrogate mechanisms of REM sleep and cataplexy.