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Effects of pedunculopontine nucleus cholinergic lesion on gait and dyskinesia in hemiparkinsonian rats
European Journal of Neuroscience ( IF 3.698 ) Pub Date : 2021-01-11 , DOI: 10.1111/ejn.15106
Nicole E. Chambers 1 , Michael Coyle 1 , Jordan Sergio 1 , Kathryn Lanza 1 , Carolyn Saito 1 , Brent Topping 1 , Stewart D. Clark 2 , Christopher Bishop 1
Affiliation  

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.

中文翻译:

人足桥神经节胆碱能损伤对半帕金森病大鼠步态和运动障碍的影响

正常人动物中,柏单宁核(PPN)胆碱能神经元与步态冻结和运动定型有关,但这些神经元对特定步态参数和治疗诱发的运动障碍的因果作用仍是推测性的。因此,我们检查了鼻侧PPN的选择性胆碱能损伤是否会影响PD运动和步态缺陷,L‐DOPA引起的运动障碍和运动改善以及DA激动剂引起的运动障碍。将Sprague-Dawley大鼠分为一个单侧病变组:假病变,PPN胆碱能性病变与白喉尿紧张素II融合毒素,内侧前脑束多巴胺病变与6-羟基多巴胺或乙酰胆碱和多巴胺双重病变。我们使用步态分析和前爪调整步骤来检查PD步态和运动功能障碍。前爪调节步骤也用于评估L‐DOPA治疗对运动的改善。异常的非自愿运动量表测量了L-DOPA和多巴胺D1和D2受体激动剂引起的运动障碍。经酪氨酸羟化酶和胆碱乙酰基转移酶免疫组织化学证实的病变分别平均减少了95%的黑质多巴胺神经元和80%的PPN胆碱能神经元。接受乙酰胆碱和双重损伤的大鼠表现出增强的冰冻,乙酰胆碱损伤的大鼠表现出增加的印刷面积和站立指数。多巴胺和双病变在L-DOPA上和下产生了相似的前爪调节步骤。相对于DA损伤的大鼠,双损伤的大鼠在特定时间点显示L-DOPA和DA激动剂引起的运动障碍减少。我们的结果表明,PPN胆碱能神经元影响与姿势稳定性有关的步态参数。因此,以治疗性靶向PPN胆碱能神经元可以减少PD中顽固的姿势不稳定性,而不会影响运动益处或L-DOPA治疗的副作用。
更新日期:2021-01-11
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