Optogenetic Stimulation of GABAergic Neurons in the Globus Pallidus Produces Hyperkinesia.
Optogenetic Stimulation of GABAergic Neurons in the Globus Pallidus Produces Hyperkinesia.
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苍白球 GABA 能神经元的光遗传学刺激产生运动亢进
DOI：
10.3389/fnbeh.2018.00185
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发表时间：
2018
影响因子：
3
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Tian J;Yan Y;Xi W;Zhou R;Lou H;Duan S;Chen JF;Zhang B
苍白球（GP）正在成为基底神经节控制运动活动的关键部位，但GABA能GP神经元的确切作用仍有待确定。利用VGAT-ChR 2-EYFP转基因小鼠，通过在GABA能神经元中靶向表达通道视紫红质2（ChR 2），我们表明，在右侧GP中GABA能神经元的光遗传学刺激产生运动亢进。光遗传刺激GABA能GP神经元使GP、M1皮质和尾壳核（CPu）的c-Fos阳性细胞数增加，脚内核（EPN）的c-Fos阳性细胞数减少。与经典的基底神经节模型一致。此外，我们将AAV-CaMK II α-ChR 2-mCherry病毒递送到丘脑底核（subthalamic nucleus，GNF）的兴奋性神经元，并选择性地刺激从GNF到GP的多巴胺能传入纤维。这种光遗传学刺激产生了异常运动，类似于在VGAT-ChR 2-EYFP转基因小鼠中观察到的行为。同时，我们发现，c-Fos在GP，M1，EPN，CPu中的表达模式与VGAT-ChR 2-EYFP转基因小鼠中的c-Fos表达模式相似。总之，我们的研究结果表明，过量的GP GABA能神经元活动可能是多动性运动障碍中异常不自主运动的神经基质。异常不自主运动背后的神经回路与过度的GP、M1、CPu活动和减少的EPN活动相关。抑制GP GABA能神经元代表了多动性运动障碍的新治疗靶点。
The globus pallidus (GP) is emerging as a critical locus of basal ganglia control of motor activity, but the exact role of GABAergic GP neurons remain to be defined. By targeted expression of channelrhodopsin 2 (ChR2) in GABAergic neurons using the VGAT-ChR2-EYFP transgenic mice, we showed that optogenetic stimulation of GABAergic neurons in the right GP produced hyperkinesia. Optogenetic stimulation of GABAergic GP neurons increased c-Fos-positive cells in GP, M1 cortex, and caudate-putamen (CPu), and decreased c-Fos-positive cells in entopeduncular nucleus (EPN), compared to the contralateral hemisphere. In agreement with the canonical basal ganglia model. Furthermore, we delivered AAV-CaMKIIα-ChR2-mCherry virus to the excitatory neurons of the subthalamic nucleus (STN) and selectively stimulated glutamatergic afferent fibers from the STN onto the GP. This optogenetic stimulation produced abnormal movements, similar to the behaviors that observed in the VGAT-ChR2-EYFP transgenic mice. Meanwhile, we found that the c-Fos expression pattern in the GP, M1, STN, EPN, and CPu produced by optogenetic activation of glutamatergic afferent fibers from the STN in GP was similar to the c-Fos expression pattern in the VGAT-ChR2-EYFP transgenic mice. Taken together, our results suggest that excess GP GABAergic neurons activity could be the neural substrate of abnormal involuntary movements in hyperkinetic movement disorders. The neural circuitry underlying the abnormal involuntary movements is associated with excessive GP, M1, CPu activity, and reduced EPN activity. Inhibition of GP GABAergic neurons represents new treatment targets for hyperkinetic movement disorder.
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