PT  - JOURNAL ARTICLE
AU  - Carrie E. Mahoney
AU  - Lindsay J. Agostinelli
AU  - Jessica N. K. Brooks
AU  - Bradford B. Lowell
AU  - Thomas E. Scammell
TI  - GABAergic neurons of the central amygdala promote cataplexy
AID  - 10.1523/JNEUROSCI.4065-15.2017
DP  - 2017 Feb 24
TA  - The Journal of Neuroscience
PG  - 4065-15
4099  - http://www.jneurosci.org/content/early/2017/02/24/JNEUROSCI.4065-15.2017.short
4100  - http://www.jneurosci.org/content/early/2017/02/24/JNEUROSCI.4065-15.2017.full
AB  - Narcolepsy is characterized by chronic sleepiness and cataplexy — sudden muscle paralysis triggered by strong, positive emotions. Narcolepsy 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. As 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 AAVs coding for Cre-dependent DREADDs or a control vector into the CeA of orexin knockout 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 CNO under baseline conditions and under conditions that should elicit positive emotions. In mice expressing hM3, CNO roughly doubled the amount of cataplexy in the first 3 hours 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. 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.