Department of Psychology, Behavioral Neuroscience Program, Binghamton University, Binghamton, NY, USA.
Department of Pharmacology and Toxicology, Jacobs School of Medicine & Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Eur J Neurosci. 2021 Apr;53(8):2835-2847. doi: 10.1111/ejn.15106. Epub 2021 Jan 24.
Pedunculopontine nucleus (PPN) cholinergic neurons are implicated in freezing of gait in Parkinson's disease (PD) and motor stereotypy in normal animals, but the causal role of these neurons on specific gait parameters and treatment-induced dyskinesia remains speculative. Therefore, we examined whether selective cholinergic lesion of the rostral PPN affects PD motor and gait deficits, L-DOPA-induced dyskinesia and motor improvement, and DA-agonist-induced dyskinesia. Sprague-Dawley rats were assigned to one unilaterally lesioned group: Sham lesion, PPN cholinergic lesion with diphtheria urotensin II fusion toxin, medial forebrain bundle dopamine lesion with 6-hydroxydopamine, or dual acetylcholine and dopamine lesion. We used gait analysis and forepaw adjusting steps to examine PD gait and motor deficits. Forepaw adjusting steps were also used to assess motor improvement with L-DOPA treatment. The abnormal involuntary movements scale measured L-DOPA and dopamine D1- and D2-receptor agonist-induced dyskinesia. Lesions, verified via tyrosine hydroxylase and choline acetyltransferase immunohistochemistry reduced an average of 95% of nigral dopamine neurons and 80% of PPN cholinergic neurons, respectively. Rats receiving acetylcholine and dual lesion demonstrated enhanced freezing, and acetylcholine lesioned rats exhibited increased print area and stand index. Dopamine and dual lesion produced similar forepaw adjusting steps task on and off L-DOPA. Relative to DA lesioned rats, dual lesioned rats displayed reduced L-DOPA and DA agonist-induced dyskinesia at specific time points. Our results indicate that PPN cholinergic neurons affect gait parameters related to postural stability. Therefore, therapeutically targeting PPN cholinergic neurons could reduce intractable postural instability in PD without affecting motor benefits or side effects of L-DOPA treatment.
被盖部脑桥核（PPN）胆碱能神经元被认为与帕金森病（PD）中的步态冻结和正常动物中的运动刻板有关，但这些神经元对特定步态参数和治疗引起的运动障碍的因果作用仍存在推测。因此，我们研究了选择性胆碱能损伤 rostral PPN 是否会影响 PD 运动和步态缺陷、L-DOPA 诱导的运动障碍和运动改善以及 DA 激动剂诱导的运动障碍。Sprague-Dawley 大鼠被分配到一个单侧损伤组：假损伤、用白喉 Urotensin II 融合毒素损伤 PPN 胆碱能神经元、用 6-羟多巴胺损伤内侧前脑束多巴胺神经元或双重乙酰胆碱和多巴胺损伤。我们使用步态分析和前爪调整步骤来检查 PD 步态和运动缺陷。前爪调整步骤也用于评估 L-DOPA 治疗的运动改善。异常不自主运动量表测量 L-DOPA 和多巴胺 D1 和 D2 受体激动剂诱导的运动障碍。酪氨酸羟化酶和胆碱乙酰转移酶免疫组织化学验证的损伤分别减少了黑质多巴胺神经元的平均 95%和 PPN 胆碱能神经元的 80%。接受乙酰胆碱和双重损伤的大鼠表现出增强的冻结，而乙酰胆碱损伤的大鼠表现出增加的打印面积和站立指数。多巴胺和双重损伤在 L-DOPA 开和关时产生类似的前爪调整步骤任务。与 DA 损伤的大鼠相比，双重损伤的大鼠在特定时间点显示出减少的 L-DOPA 和 DA 激动剂诱导的运动障碍。我们的结果表明，PPN 胆碱能神经元影响与姿势稳定性相关的步态参数。因此，靶向 PPN 胆碱能神经元治疗可能会减少 PD 中的难治性姿势不稳定，而不会影响 L-DOPA 治疗的运动益处或副作用。
