title: GABA Cells in the Central Nucleus of the Amygdala Promote Cataplexy.
abstract: Cataplexy is a hallmark of narcolepsy characterized by the sudden uncontrollable onset of muscle weakness or paralysis during wakefulness. It can occur spontaneously, but is typically triggered by positive emotions such as laughter. Although cataplexy was identified >130 years ago, its neural mechanism remains unclear. Here, we show that a newly identified GABA circuit within the central nucleus of the amygdala (CeA) promotes cataplexy. We used behavioral, electrophysiological, immunohistochemical, and chemogenetic strategies to target and manipulate CeA activity selectively in narcoleptic (orexin-/-) mice to determine its functional role in controlling cataplexy. First, we show that chemogenetic activation of the entire CeA produces a marked increase in cataplexy attacks. Then, we show that GABA cells within the CeA are responsible for mediating this effect. To manipulate GABA cells specifically, we developed a new mouse line that enables genetic targeting of GABA cells inorexin-/-mice. We found that chemogenetic activation of GABA CeA cells triggered a 253% increase in the number of cataplexy attacks without affecting their duration, suggesting that GABA cells play a functional role in initiating but not maintaining cataplexy. We show that GABA cell activation only promotes cataplexy attacks associated with emotionally rewarding stimuli, not those occurring spontaneously. However, we found that chemogenetic inhibition of GABA CeA cells does not prevent cataplexy, suggesting these cells are not required for initiating cataplexy attacks. Our results indicate that the CeA promotes cataplexy onset and that emotionally rewarding stimuli may trigger cataplexy by activating GABA cells in the CeA.SIGNIFICANCE STATEMENTAlthough cataplexy has been closely linked to positive emotions for >130 years, the neural circuitry that underlies this relationship is poorly understood. Recent work suggests that the amygdala, a brain area important for processing emotion, may be part of this circuit. This study provides the first functional evidence to implicate GABA cells in the amygdala as regulators of cataplexy triggered by positive emotions and identifies the amygdala as the brain region important more for gating the entrance into rather than the exit from cataplexy. We also generated a new mouse model for studying GABA neurons in narcoleptic mice, which could serve as a useful tool for studying the neurobiological underpinnings of narcolepsy.
authors.affiliation: Centre for Biological Timing and Cognition.|Department of Cell and Systems Biology.
authors.forename: Matthew B
authors.identifier: 0000-0001-5924-7444
authors.initials: MB
authors.lastname: Snow
authors.affiliation: Centre for Biological Timing and Cognition.|Department of Cell and Systems Biology.
authors.forename: Jimmy J
authors.initials: JJ
authors.lastname: Fraigne
authors.affiliation: Centre for Biological Timing and Cognition.|Department of Cell and Systems Biology.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Thibault-Messier
authors.affiliation: Centre for Biological Timing and Cognition.|Department of Cell and Systems Biology.
authors.forename: Victoria L
authors.identifier: 0000-0001-6687-2600
authors.initials: VL
authors.lastname: Chuen
authors.affiliation: Centre for Biological Timing and Cognition.|Department of Cell and Systems Biology.
authors.forename: Aren
authors.identifier: 0000-0003-1338-7294
authors.initials: A
authors.lastname: Thomasian
authors.affiliation: Department of Medicine, and.|Department of Physiology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Horner
authors.affiliation: Centre for Biological Timing and Cognition, john.peever@utoronto.ca.|Department of Cell and Systems Biology.|Department of Physiology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Peever
mesh_terms: D000818:Animals; D002385:Cataplexy / Q000378:metabolism* / Q000503:physiopathology; D066274:Central Amygdaloid Nucleus / Q000378:metabolism* / Q000503:physiopathology; D004569:Electroencephalography / Q000379:methods; D059330:GABAergic Neurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000068797:Orexins / Q000172:deficiency
chemical_list: D000068797:Orexins
keywords: amygdala; cataplexy; chemogenetics; narcolepsy; sleep