Narcolepsy with cataplexy affects 1:2,000 Americans, yet little is known about the neural pathways that control cataplexy - episodes of muscle paralysis that are often triggered by positive emotions. The neuropeptide orexin (hypocretin) clearly plays a central role in this system because people, dogs, and mice with deficient orexin signaling have narcolepsy with cataplexy. We and others have made good progress identifying the factors that regulate the activity of the orexin neurons, and we now plan to investigate how the orexin neurons suppress cataplexy. Using mouse models of narcolepsy, we will apply powerful genetic, anatomic, and physiologic techniques to define the complex neural circuits that underlie cataplexy. To determine whether mouse cataplexy is similar to that seen in people with narcolepsy, we will test whether mouse cataplexy is triggered by positive emotions and drugs known to affect human cataplexy. Next, we will define the neurochemical systems through which orexin suppresses cataplexy by studying orexin receptor knock-in mice that produce orexin receptors only in neurons producing catecholamines, serotonin, or dopamine D2 receptors. To define the brain regions through which orexin suppresses cataplexy, we will microinject an adeno-associated viral vector containing Cre recombinase into specific brainstem regions of these orexin receptor knock-in mice, thus inducing focal expression of orexin receptors and rescuing the cataplexy phenotype. Last, we will use anterograde and retrograde tracing techniques to map the neural pathways through which orexin suppresses cataplexy. By physiologically and anatomically defining the pathways through which orexin suppresses cataplexy, we will gain novel insights into the neurobiology of atonia that should lead to more effective and rational therapies for cataplexy, narcolepsy, and other disorders of motor control.
| Kantor, Sandor; Mochizuki, Takatoshi; Lops, Stefan N et al. (2013) Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice. Sleep 36:1129-38 |
| Oishi, Yo; Williams, Rhiannan H; Agostinelli, Lindsay et al. (2013) Role of the medial prefrontal cortex in cataplexy. J Neurosci 33:9743-51 |
| Burgess, Christian R; Oishi, Yo; Mochizuki, Takatoshi et al. (2013) Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci 33:9734-42 |
| Saper, Clifford B; Romanovsky, Andrej A; Scammell, Thomas E (2012) Neural circuitry engaged by prostaglandins during the sickness syndrome. Nat Neurosci 15:1088-95 |
| Burgess, Christian R; Scammell, Thomas E (2012) Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci 32:12305-11 |
| Espana, Rodrigo A; Scammell, Thomas E (2011) Sleep neurobiology from a clinical perspective. Sleep 34:845-58 |
| Mochizuki, Takatoshi; Arrigoni, Elda; Marcus, Jacob N et al. (2011) Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci U S A 108:4471-6 |
| Scammell, Thomas E; Winrow, Christopher J (2011) Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51:243-66 |
| Lim, Andrew S P; Scammell, Thomas E (2010) The trouble with Tribbles: do antibodies against TRIB2 cause narcolepsy? Sleep 33:857-8 |
| Diniz Behn, Cecilia G; Klerman, Elizabeth B; Mochizuki, Takatoshi et al. (2010) Abnormal sleep/wake dynamics in orexin knockout mice. Sleep 33:297-306 |
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