Ionic Mechanisms Underlying the Excitatory Effect of Orexin on Rat Subthalamic Nucleus Neurons
Ionic Mechanisms Underlying the Excitatory Effect of Orexin on Rat Subthalamic Nucleus Neurons
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食欲素对大鼠丘脑底核神经元兴奋作用的离子机制
DOI：
10.3389/fncel.2019.00153
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发表时间：
2019-04-24
影响因子：
5.3
通讯作者：
Zhu, Jing-Ning
中科院分区：
文献类型：
--
作者：
Li, Guang-Ying;Zhuang, Qian-Xing;Zhu, Jing-Ning
中枢食欲素系统缺陷会导致猝倒，这是一种以肌张力突然丧失为特征的运动缺陷，凸显了食欲素在运动控制中的直接调节作用。然而，食欲素调节运动功能的神经机制仍然很大程度上未知。丘脑底核（STN）是基底神经节唯一的兴奋性结构，在基底神经节电路和运动控制中占有关键地位。先前的研究表明，包括 STN 在内的基底神经节中广泛分布着食欲素能纤维和食欲素受体。因此，本研究利用全细胞膜片钳记录和免疫染色技术，研究了食欲素对脑切片中STN神经元的直接影响，特别是潜在的受体和离子机制。我们的结果表明，orexin-A 对大鼠 STN 神经元产生兴奋作用。河豚毒素 (TTX) 不会阻断食欲素诱导的 STN 神经元兴奋，表明神经肽具有直接的突触后作用。 STN 神经元上的食欲素 A 诱导的内向电流是由 OX1 和 OX2 受体的激活介导的。免疫荧光结果显示OX1和OX2受体在STN神经元中共表达并共定位。此外，Na+-Ca2+交换器（NCX）和内向整流K+通道共同介导食欲素-A对STN神经元的兴奋作用。这些结果证明了食欲素对 STN 神经元的兴奋作用背后的双重受体与下游离子机制的结合，表明中枢食欲素能系统对基底神经节回路及其相关运动控制和运动疾病的潜在调节。
Central orexinergic system deficiency results in cataplexy, a motor deficit characterized with a sudden loss of muscle tone, highlighting a direct modulatory role of orexin in motor control. However, the neural mechanisms underlying the regulation of orexin on motor function are still largely unknown. The subthalamic nucleus (STN), the only excitatory structure of the basal ganglia, holds a key position in the basal ganglia circuitry and motor control. Previous study has revealed a wide distribution of orexinergic fibers as well as orexin receptors in the basal ganglia including the STN. Therefore, in the present study, by using whole-cell patch clamp recording and immunostaining techniques, the direct effect of orexin on the STN neurons in brain slices, especially the underlying receptor and ionic mechanisms, were investigated. Our results show that orexin-A elicits an excitatory effect on STN neurons in rats. Tetrodotoxin (TTX) does not block the orexin-induced excitation on STN neurons, suggesting a direct postsynaptic action of the neuropeptide. The orexin-A-induced inward current on STN neurons is mediated by the activation of both OX1 and OX2 receptors. Immunofluorescence result shows that OX1 and OX2 receptors are co-expressed and co-localized in STN neurons. Furthermore, Na+-Ca2+ exchangers (NCXs) and inward rectifier K+ channels co-mediate the excitatory effect of orexin-A on STN neurons. These results demonstrate a dual receptor in conjunction with the downstream ionic mechanisms underlying the excitatory action of orexin on STN neurons, suggesting a potential modulation of the central orexinergic system on basal ganglia circuitry as well as its related motor control and motor diseases.