Parkinsonian motor deficits are associated with elevated inhibitory output from the basal ganglia (BG). However, several features of Parkinson's disease (PD) have not been accounted for by this simple "classical rate model" framework, including the observation in PD patients that movements guided by external stimuli are less impaired than otherwise-identical movements generated based on internal goals. Is this difference due to divergent processing within the BG itself, or to the recruitment of extra-BG pathways by sensory processing? In addition, surprisingly little is known about precisely when, in the sequence from selecting to executing movements, BG output is altered by PD. Here, we address these questions by recording activity in the SNr, a key BG output nucleus, in hemiparkinsonian mice performing a well-controlled behavioral task requiring stimulus-guided and internally-specified directional movements. We found that hemiparkinsonian mice exhibited a bias ipsilateral to the side of dopaminergic cell loss that was stronger when movements were internally specified rather than stimulus guided, consistent with clinical observations in parkinsonian patients. We further found that changes in parkinsonian SNr activity during movement preparation were consistent with the ipsilateral behavioral bias, as well as its greater magnitude for internally-specified movements. While these findings are inconsistent with some aspects of the classical rate model, they are accounted for by a related "directional rate model" positing that SNr output phasically over-inhibits motor output in a direction-specific manner. These results suggest that parkinsonian changes in BG output underlying movement preparation contribute to the greater deficit in internally-specified than stimulus-guided movements.

中文翻译：

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偏侧帕金森病小鼠运动准备期间基底神经节输出中断与行为缺陷一致

帕金森病运动缺陷与基底神经节 (BG) 的抑制输出升高有关。然而，这种简单的“经典速率模型”框架尚未解释帕金森病 (PD) 的几个特征，包括在 PD 患者中观察到，由外部刺激引导的运动比基于内部目标产生的其他相同运动受到的损害更小。这种差异是由于 BG 本身内部的不同处理造成的，还是由于感觉处理招募了额外的 BG 通路？此外，令人惊讶的是，我们对在从选择到执行动作的顺序中，BG 输出何时被 PD 改变的确切时间知之甚少。在这里，我们通过记录 SNr 的活动来解决这些问题，SNr 是一个关键的 BG 输出核，在偏侧帕金森病小鼠中执行需要刺激引导和内部指定方向运动的良好控制的行为任务。我们发现，偏侧帕金森病小鼠表现出对多巴胺能细胞损失一侧的同侧偏差，当运动是内部指定的而不是刺激引导时，这种偏差更强，这与帕金森病患者的临床观察结果一致。我们进一步发现，运动准备期间帕金森 SNr 活动的变化与同侧行为偏差一致，并且其内部指定运动的幅度更大。虽然这些发现与经典速率模型的某些方面不一致，但它们可以通过相关的“方向速率模型”来解释，该模型假设 SNr 输出以特定方向的方式阶段性地过度抑制运动输出。