Kase Daisuke, Zimnik Andrew J, Han Yan, Harsch Devin R, Bacha Sarah, Cox Karin M, Bostan Andreea C, Richardson R Mark, Turner Robert S
Department of Neurobiology, Center for Neuroscience and The Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, United States.
J Neurophysiol. 2025 Aug 1;134(2):741-765. doi: 10.1152/jn.00611.2024. Epub 2025 Jul 22.
Although the basal ganglia (BG) play a central role in the motor symptoms of Parkinson's disease, few studies have investigated the influence of parkinsonism on movement-related activity in the BG. Here, we studied the perimovement activity of neurons in globus pallidus internus (GPi) of nonhuman primates (NHPs) during performance of a choice reaction time reaching task before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal responses, including increases or decreases in firing rate, were equally common in the parkinsonian brain as seen before MPTP, and the distribution of different response types was largely unchanged. The slowing of behavioral reaction times and movement durations following the induction of parkinsonism was accompanied by a prolongation of the time interval between neuronal response onset and movement initiation. Neuronal responses were also reduced in magnitude and prolonged in duration after the induction of parkinsonism. Importantly, those two effects were more pronounced among decrease-type responses, and they persisted after controlling for MPTP-induced changes in the between-trial variability in response timing. Following MPTP, the trial-to-trial timing of neuronal responses also became uncoupled from the time of movement onset and more variable in general. Overall, the effects of MPTP on temporal features of GPi responses were related to the severity of parkinsonian motor impairments, whereas changes in response magnitude and duration did not reflect symptom severity consistently. These findings point to a previously underappreciated potential role for abnormalities in the timing of GPi task-related activity in the generation of parkinsonian motor signs. Although the globus pallidus internus (GPi) plays a central role in the cardinal symptoms of Parkinson's disease (PD), how parkinsonism alters the movement-related activity of GPi neurons remains understudied. Using a monkey model of PD, we found that: ) the timing of GPi responses became uncoupled from movement onset; and ) responses, especially decrease-type responses, became attenuated and prolonged. These abnormalities in GPi perimovement activity may contribute to the generation of parkinsonian motor signs.
尽管基底神经节（BG）在帕金森病的运动症状中起核心作用，但很少有研究调查帕金森症对BG中与运动相关活动的影响。在此，我们研究了非人灵长类动物（NHPs）在注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱发帕金森症前后，在执行选择反应时伸手任务期间苍白球内侧部（GPi）神经元的运动周围活动。包括放电率增加或减少在内的神经元反应，在帕金森病大脑中与MPTP注射前一样常见，并且不同反应类型的分布基本未变。帕金森症诱发后行为反应时间和运动持续时间的减慢，伴随着神经元反应开始与运动启动之间时间间隔的延长。帕金森症诱发后，神经元反应的幅度也降低，持续时间延长。重要的是，这两种效应在减少型反应中更为明显，并且在控制了MPTP引起的反应时间试验间变异性变化后仍然存在。注射MPTP后，神经元反应的逐次试验时间也与运动开始时间解耦，总体上更具变异性。总体而言，MPTP对GPi反应时间特征的影响与帕金森病运动障碍的严重程度有关，而反应幅度和持续时间的变化并不能始终反映症状严重程度。这些发现指出了GPi任务相关活动时间异常在帕金森病运动体征产生中一个此前未被充分认识的潜在作用。尽管苍白球内侧部（GPi）在帕金森病（PD）的主要症状中起核心作用，但帕金森症如何改变GPi神经元的运动相关活动仍未得到充分研究。使用帕金森病猴子模型，我们发现：）GPi反应的时间与运动开始解耦；并且）反应，尤其是减少型反应，变得减弱和延长。GPi运动周围活动的这些异常可能有助于帕金森病运动体征的产生。
