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 in orexin^-/- 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 STATEMENT Although 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.

Keywords: amygdala; cataplexy; chemogenetics; narcolepsy; sleep.