Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.
Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.
复制标题
通过基础神经节电路的光遗传控制对帕金森运动行为的调节。
作者：
基底神经节的神经回路对于运动规划和动作选择至关重要。已经描述了两个平行的基底神经节通路，它们被提出对运动功能施加相反的影响。根据这一经典模型，直接途径的激活促进运动，间接途径的激活抑制运动。然而，最近的解剖学和功能证据对这一假设的有效性提出了质疑。因为这个模型从未经过经验检验，这些回路在动物行为中的具体功能仍然未知。在这里，我们直接激活基底神经节电路在体内，使用直接和间接途径介质棘投射神经元（MSN）的光遗传学控制，通过Cre依赖性病毒表达的通道视紫红质-2在D1-Cre和D2-Cre BAC转基因小鼠的纹状体。间接通路MSNs的双侧兴奋引起帕金森病状态，其特征是增加冻结，运动迟缓，减少运动启动。相比之下，激活直接途径的MSN减少冻结和增加运动。在帕金森病小鼠模型中，直接途径激活完全挽救了冻结、运动迟缓和运动启动的缺陷。总之，我们的研究结果建立了一个关键的作用，基底神经节电路的双向调节运动行为，并表明，调制直接通路电路可能是一种有效的治疗策略，改善帕金森氏症的运动缺陷。
Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, which are proposed to exert opposing influences on motor function. According to this classical model, activation of the direct pathway facilitates movement and activation of the indirect pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here, we directly activated basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of D1-Cre and D2-Cre BAC transgenic mice. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia, and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct pathway activation completely rescued deficits in freezing, bradykinesia, and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behavior and indicate that modulation of direct pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.
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