背景:长期使用左旋多巴治疗帕金森病(PD)往往受到运动并发症发展的阻碍,包括左旋多巴诱导的运动障碍(LID)。黑质网状结构(SNr)和苍白球内段(GPi)是基底神经节的输出核。SNr和GPi活性的失调有助于PD病理生理学和LID。
目的:本研究的目的是确定在小鼠模型中SNrGABA能神经元和SNr投射对足桥脑核(PPN)的直接调节是否调节PD症状和LID。
方法:我们在Vgat-IRES-Cre小鼠的SNrGABA能神经元中选择性表达了Cre重组酶激活的通道视紫红质2(ChR2)或卤代视紫红质腺相关病毒2(AAV2)载体。6-羟基多巴胺PD模型中的Cre小鼠,以研究SNr神经元的直接光遗传调节或其对PPIDPD表达的投射是否前爪踏步任务,鼠标LID评定量表,和开场运动用于评估运动障碍和LID以测试SNr调制的效果。
结果:通过用卤化视紫红质抑制SNr神经元活性,运动障碍得到改善。通过使用ChR2增加SNr神经元活性,LID显着降低,而ChR2不会干扰左旋多巴的抗运动作用。SNr投射中ChR2的光学刺激对PPN的直接刺激。
结论:SNrGABA能神经元的调节以与基底神经节回路速率模型一致的方式改变运动障碍和LID表达。此外,从SNr到PPN的投射可能介导增加SNr神经元活性的抗运动障碍作用,确定PPN在LID中的潜在新作用。©2023作者。由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
Long-term use of levodopa for Parkinson\'s disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID.
The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model.
We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation.
Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation.
Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.