title: GABAergic Neurons of the Central Amygdala Promote Cataplexy.
abstract: Narcolepsy is characterized by chronic sleepiness and cataplexy-sudden muscle paralysis triggered by strong, positive emotions. This condition is caused by a lack of orexin (hypocretin) signaling, but little is known about the neural mechanisms that mediate cataplexy. The amygdala regulates responses to rewarding stimuli and contains neurons active during cataplexy. In addition, lesions of the amygdala reduce cataplexy. Because GABAergic neurons of the central nucleus of the amygdala (CeA) target brainstem regions known to regulate muscle tone, we hypothesized that these cells promote emotion-triggered cataplexy. We injected adeno-associated viral vectors coding for Cre-dependent DREADDs or a control vector into the CeA of orexin knock-out mice crossed with vGAT-Cre mice, resulting in selective expression of the excitatory hM3 receptor or the inhibitory hM4 receptor in GABAergic neurons of the CeA. We measured sleep/wake behavior and cataplexy after injection of saline or the hM3/hM4 ligand clozapine-N-oxide (CNO) under baseline conditions and under conditions that should elicit positive emotions. In mice expressing hM3, CNO approximately doubled the amount of cataplexy in the first 3 h after dosing under baseline conditions. Rewarding stimuli (chocolate or running wheels) also increased cataplexy, but CNO produced no further increase. In mice expressing hM4, CNO reduced cataplexy in the presence of chocolate or running wheels. These results demonstrate that GABAergic neurons of the CeA are sufficient and necessary for the production of cataplexy in mice, and they likely are a key part of the mechanism through which positive emotions trigger cataplexy.SIGNIFICANCE STATEMENTCataplexy is one of the major symptoms of narcolepsy, but little is known about how strong, positive emotions trigger these episodes of muscle paralysis. Prior research shows that amygdala neurons are active during cataplexy and cataplexy is reduced by lesions of the amygdala. We found that cataplexy is substantially increased by selective activation of GABAergic neurons in the central nucleus of the amygdala (CeA). We also demonstrate that inhibition of these neurons reduces reward-promoted cataplexy. These results build upon prior work to establish the CeA as a crucial element in the neural mechanisms of cataplexy. These results demonstrate the importance of the CeA in regulating responses to rewarding stimuli, shedding light on the broader neurobiology of emotions and motor control.
authors.affiliation: Department of Neurology and.
authors.forename: Carrie E
authors.identifier: 0000-0003-0094-2500
authors.initials: CE
authors.lastname: Mahoney
authors.affiliation: Department of Neurology and.
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Agostinelli
authors.affiliation: Department of Neurology and.
authors.forename: Jessica N K
authors.identifier: 0000-0003-2892-4195
authors.initials: JN
authors.lastname: Brooks
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.affiliation: Department of Neurology and tscammel@bidmc.harvard.edu.
authors.forename: Thomas E
authors.identifier: 0000-0002-7231-8558
authors.initials: TE
authors.lastname: Scammell
mesh_terms: D000818:Animals; D002385:Cataplexy / Q000235:genetics* / Q000378:metabolism*; D066274:Central Amygdaloid Nucleus / Q000378:metabolism*; D059330:GABAergic Neurons / Q000378:metabolism*; D008124:Locomotion / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
keywords: DREADDs; cataplexy; hypocretin; mouse; narcolepsy; orexin