Immunotoxin-mediated tract targeting in the primate brain: selective elimination of the cortico-subthalamic "hyperdirect" pathway.
Immunotoxin-mediated tract targeting in the primate brain: selective elimination of the cortico-subthalamic "hyperdirect" pathway.
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DOI：
10.1371/journal.pone.0039149
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Takada M
中科院分区：
文献类型：
--
作者：
Inoue K;Koketsu D;Kato S;Kobayashi K;Nambu A;Takada M
使用神经元特异性逆行基因转移载体（NeuRet载体），我们在灵长类动物大脑中建立了免疫毒素（IT）介导的道靶向，允许消融构成特定通路的神经元群体。在这里，我们试图选择性地去除皮质-丘脑底核的“超直接”通路。超直接通路与直接通路和间接通路一起，在基底神经节的运动信息处理中起着至关重要的作用。这条通路将额叶的运动相关区域直接连接到丘脑底核（subthalamic nucleus，简称丘脑底核），而不需要纹状体的中继。在运动相关区域如辅助运动区（SMA）中的电刺激后，通常在苍白球（GPi）的内部段中检测到由早期兴奋、抑制和晚期兴奋组成的三相反应。一些药理生理学证据表明，早期兴奋可能来自超直接途径。在本研究中，将表达人白细胞介素-2受体α亚基的NeuRet载体注射到猕猴的脊髓中。然后，将IT注射到SMA中。在这些猴子中，记录了GPi中响应SMA刺激的单神经元活动。我们发现，早期兴奋大大减少，无论是抑制还是后期兴奋的影响。GPi神经元的自发放电频率和模式保持不变。这表明IT介导的束靶向成功地从基底神经节回路中选择性地消除了超直接通路，而不影响轴突神经元的自发活动。从逆行和顺行神经追踪获得的解剖数据证实了电生理发现。本研究结果表明，皮层驱动的GPi神经元的早期兴奋是由超直接途径介导的。IT介导的神经束靶向技术将为我们阐明各种神经网络功能提供新的策略。
Using a neuron-specific retrograde gene-transfer vector (NeuRet vector), we established immunotoxin (IT)-mediated tract targeting in the primate brain that allows ablation of a neuronal population constituting a particular pathway. Here, we attempted selective removal of the cortico-subthalamic “hyperdirect” pathway. In conjunction with the direct and indirect pathways, the hyperdirect pathway plays a crucial role in motor information processing in the basal ganglia. This pathway links the motor-related areas of the frontal lobe directly to the subthalamic nucleus (STN) without relay at the striatum. After electrical stimulation in the motor-related areas such as the supplementary motor area (SMA), triphasic responses consisting of an early excitation, an inhibition, and a late excitation are usually detected in the internal segment of the globus pallidus (GPi). Several lines of pharmacophysiological evidence suggest that the early excitation may be derived from the hyperdirect pathway. In the present study, the NeuRet vector expressing human interleukin-2 receptor α-subunit was injected into the STN of macaque monkeys. Then, IT injections were made into the SMA. In these monkeys, single-neuron activity in the GPi was recorded in response to the SMA stimulation. We found that the early excitation was largely reduced, with neither the inhibition nor the late excitation affected. The spontaneous firing rate and pattern of GPi neurons remained unchanged. This indicates that IT-mediated tract targeting successfully eliminated the hyperdirect pathway selectively from the basal ganglia circuitry without affecting spontaneous activity of STN neurons. The electrophysiological finding was confirmed with anatomical data obtained from retrograde and anterograde neural tracings. The present results define that the cortically-driven early excitation in GPi neurons is mediated by the hyperdirect pathway. The IT-mediated tract targeting technique will provide us with novel strategies for elucidating various neural network functions.
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