Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice

To create operational criteria for polygraphic assessments of direct transitions from wake to REM sleep (DREM), as a murine analog of human cataplexy, we have analyzed DREM episodes in congenic lines of orexin/ataxin-3 transgenic [TG] mice and wild-type littermates. The sleep stage of each 10-second epoch was visually scored using our standard criteria. Specificity of DREM for narcoleptic TG mice and sensitivity to detect DREM was evaluated using different DREM criteria. We found that DREM transitions by 10-second epoch scoring are not specific for narcoleptic TG mice and also occur in WT mice during light period. These wake-to-REM transitions in WT mice (also seen in TG mice during light period) were characteristically different from DREM transitions in TG mice during dark period; they tended to occur as brief bouts of wakefulness interrupting extended episodes of REM sleep, suggesting that these transitions do not represent abnormal manifestations of REM sleep. We therefore defined the DREM transitions by requiring a minimum number of preceding wake epochs. Requiring no fewer than four consecutive epochs of wakefulness produced the best combination of specificity (95.9%) and sensitivity (66.0%). By definition, DREM in dark-period is 100% specific to narcolepsy and was 95.9% specific overall. In addition, we found that desipramine, a trycyclic anticataplectic, potently reduces DREM, while two wake-promoting compounds have moderate (D-amphetamine) and no (modafinil) effect on DREM; the effects mirror the anticataplectic effects of these compounds reported in canine and human narcolepsy. Our definition of DREM in murine narcolepsy may provide good electrophysiological measures for cataplexy-equivalent episodes.

[1]  E. Mignot,et al.  Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans , 2000, Neuroscience Research.

[2]  T. Sakurai,et al.  Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Jon T. Willie,et al.  Narcolepsy in orexin Knockout Mice Molecular Genetics of Sleep Regulation , 1999, Cell.

[4]  E. Mignot,et al.  PHARMACOLOGICAL ASPECTS OF HUMAN AND CANINE NARCOLEPSY , 1997, Progress in Neurobiology.

[5]  Sebastiaan Overeem,et al.  A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains , 2000, Nature Medicine.

[6]  Jon T. Willie,et al.  Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and Obesity , 2001, Neuron.

[7]  E. Mignot,et al.  Neuronal activity in the cholinoceptive basal forebrain of freely moving narcoleptic dobermans , 1998, Neuroreport.

[8]  C. Saper,et al.  Concomitant loss of dynorphin, NARP, and orexin in narcolepsy , 2005, Neurology.

[9]  Takeshi Sakurai,et al.  Behavioral State Instability in Orexin Knock-Out Mice , 2004, The Journal of Neuroscience.

[10]  R. Chervin,et al.  Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. , 1997, Sleep.

[11]  E. Mignot,et al.  The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. , 2002, Archives of neurology.

[12]  C. Guilleminault,et al.  Hypnagogic and Hypnopompic Hallucinations: Pathological Phenomena? , 1996, British Journal of Psychiatry.

[13]  E. Mignot,et al.  Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy , 2000, Neuropsychopharmacology.

[14]  A. Rechtschaffen,et al.  A manual of standardized terminology, technique and scoring system for sleep stages of human subjects , 1968 .

[15]  Emmanuel Mignot,et al.  The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene , 1999, Cell.

[16]  K. Ishihara,et al.  High prevalence of isolated sleep paralysis: kanashibari phenomenon in Japan. , 1987, Sleep.

[17]  E. Mignot,et al.  Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs. , 1995, Sleep.

[18]  Jon T. Willie,et al.  A consensus definition of cataplexy in mouse models of narcolepsy. , 2009, Sleep.

[19]  M. Kryger,et al.  Principles and Practice of Sleep Medicine , 1989 .

[20]  T. Scammell,et al.  The neurobiology, diagnosis, and treatment of narcolepsy , 2003, Annals of neurology.

[21]  E. Mignot,et al.  Hypocretin Levels in Sporadic and Familial Cases of Canine Narcolepsy , 2001, Neurobiology of Disease.

[22]  R. Daroff,et al.  The International Classification of Sleep Disorders , 1991, Neurology.

[23]  Michael Aldrich,et al.  Reduced Number of Hypocretin Neurons in Human Narcolepsy , 2000, Neuron.

[24]  T. Scammell,et al.  Running promotes wakefulness and increases cataplexy in orexin knockout mice. , 2007, Sleep.

[25]  A. Besset,et al.  Modafinil: a double-blind multicentric study. , 1994, Sleep.

[26]  A. Rechtschaffen.  A manual of Standardized Terminology , 1968 .

[27]  C. Kushida,et al.  Electroencephalographic correlates of cataplectic attacks in narcoleptic canines. , 1985, Electroencephalography and clinical neurophysiology.

[28]  Sebastiaan Overeem,et al.  Hypocretin (orexin) deficiency in human narcolepsy , 2000, The Lancet.