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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055367-09
Application #
7806484
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Mitler, Merrill
Project Start
2000-12-01
Project End
2012-03-31
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$368,157
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Saper, Clifford B; Romanovsky, Andrej A; Scammell, Thomas E (2012) Neural circuitry engaged by prostaglandins during the sickness syndrome. Nat Neurosci 15:1088-95
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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