Li Yuhui, Lee Sung-Ho, Yu Chunxiu, Hsu Li-Ming, Wang Tzu-Wen W, Do Khoa, Kim Hyeon-Joong, Shih Yen-Yu Ian, Grill Warren M
bioRxiv. 2024 Feb 27:2024.02.22.581627. doi: 10.1101/2024.02.22.581627.
While deep brain stimulation (DBS) is widely employed for managing motor symptoms in Parkinson's disease (PD), its exact circuit mechanisms remain controversial. To identify the neural targets affected by therapeutic DBS in PD, we analyzed DBS-evoked whole brain activity in female hemi-parkinsonian rats using function magnetic resonance imaging (fMRI). We delivered subthalamic nucleus (STN) DBS at various stimulation pulse repetition rates using optogenetics, allowing unbiased examinations of cell-type specific STN feed-forward neural activity. Unilateral STN optogenetic stimulation elicited pulse repetition rate-dependent alterations of blood-oxygenation-level-dependent (BOLD) signals in SNr (substantia nigra pars reticulata), GP (globus pallidus), and CPu (caudate putamen). Notably, these manipulations effectively ameliorated pathological circling behavior in animals expressing the kinetically faster Chronos opsin, but not in animals expressing ChR2. Furthermore, mediation analysis revealed that the pulse repetition rate-dependent behavioral rescue was significantly mediated by optogenetically induced activity changes in GP and CPu, but not in SNr. This suggests that the activation of GP and CPu are critically involved in the therapeutic mechanisms of STN DBS.
虽然深部脑刺激（DBS）被广泛用于治疗帕金森病（PD）的运动症状，但其确切的神经回路机制仍存在争议。为了确定治疗性DBS在PD中影响的神经靶点，我们使用功能磁共振成像（fMRI）分析了雌性半帕金森病大鼠中DBS诱发的全脑活动。我们使用光遗传学以不同的刺激脉冲重复率进行丘脑底核（STN）DBS，从而能够对细胞类型特异性的STN前馈神经活动进行无偏倚检查。单侧STN光遗传学刺激引起黑质网状部（SNr）、苍白球（GP）和尾状壳核（CPu）中血氧水平依赖（BOLD）信号的脉冲重复率依赖性改变。值得注意的是，这些操作有效改善了表达动力学更快的Chronos视蛋白的动物的病理性转圈行为，但对表达ChR2的动物无效。此外，中介分析表明，脉冲重复率依赖性的行为挽救显著由光遗传学诱导的GP和CPu活动变化介导，而非SNr。这表明GP和CPu的激活在STN DBS的治疗机制中起关键作用。
