Snow Matthew B, Fraigne Jimmy J, Thibault-Messier Gabrielle, Chuen Victoria L, Thomasian Aren, Horner Richard L, Peever John
Centre for Biological Timing and Cognition.
Department of Cell and Systems Biology.
J Neurosci. 2017 Apr 12;37(15):4007-4022. doi: 10.1523/JNEUROSCI.4070-15.2017. Epub 2017 Feb 16.
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 () 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 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. 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.
猝倒症是发作性睡病的一个标志性特征，其特点是在清醒状态下突然出现无法控制的肌肉无力或麻痹。它可以自发发生，但通常由诸如大笑等积极情绪引发。尽管猝倒症在130多年前就已被发现，但其神经机制仍不清楚。在这里，我们表明杏仁核中央核（CeA）内一个新发现的γ-氨基丁酸（GABA）回路促进了猝倒症。我们使用行为学、电生理学、免疫组织化学和化学遗传学策略，在发作性睡病小鼠中选择性地靶向和操纵CeA的活动，以确定其在控制猝倒症中的功能作用。首先，我们表明对整个CeA进行化学遗传学激活会使猝倒症发作显著增加。然后，我们表明CeA内的GABA能细胞负责介导这种效应。为了特异性地操纵GABA能细胞，我们培育了一种新的小鼠品系，能够对发作性睡病小鼠中的GABA能细胞进行基因靶向。我们发现对CeA的GABA能细胞进行化学遗传学激活会使猝倒症发作次数增加253%，而不影响其持续时间，这表明GABA能细胞在引发而非维持猝倒症中发挥功能作用。我们表明GABA能细胞激活仅促进与情感奖励刺激相关的猝倒症发作，而不促进自发发生的发作。然而，我们发现对CeA的GABA能细胞进行化学遗传学抑制并不能预防猝倒症，这表明这些细胞对于引发猝倒症发作并非必需。我们的结果表明CeA促进猝倒症发作，并且情感奖励刺激可能通过激活CeA中的GABA能细胞来触发猝倒症。尽管猝倒症在130多年来一直与积极情绪密切相关，但这种关系背后的神经回路却知之甚少。最近的研究表明，杏仁核作为一个对处理情绪很重要的脑区，可能是这个回路的一部分。这项研究提供了首个功能性证据，表明杏仁核中的GABA能细胞是由积极情绪触发的猝倒症的调节因子，并确定杏仁核是一个对控制猝倒症发作的进入而非退出更为重要的脑区。我们还生成了一种用于研究发作性睡病小鼠中GABA能神经元的新小鼠模型，这可作为研究发作性睡病神经生物学基础的有用工具。
