Pedunculopontine tegmentum cholinergic loss leads to a progressive decline in motor abilities and neuropathological changes resembling progressive supranuclear palsy.
Pedunculopontine tegmentum cholinergic loss leads to a progressive decline in motor abilities and neuropathological changes resembling progressive supranuclear palsy.
复制标题
桥脚被盖胆碱能丧失导致运动能力进行性下降和类似于进行性核上性麻痹的神经病理变化。
DOI：
10.1111/ejn.14212
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Clark,StewartD
中科院分区：
文献类型：
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作者：
MacLaren,DuncanAA;Ljungberg,TrishaL;Griffin,MeghanE;Clark,StewartD
进行性核上性麻痹（PSP）是最常见的非典型帕金森综合征。虽然PSP与帕金森病（PD）有一些共同的病理学，但PSP具有以tau聚集为特征的不同的潜在病理学。此外，PSP患者对PD药物的反应很差，并且没有有效的替代疗法。由于缺乏显示相关PSP样病理和行为缺陷的动物模型，姑息治疗和疾病改变治疗的发展受到阻碍。之前，我们的实验室发现，在大鼠中选择性去除胆碱能脚桥脑神经元（其轴突投射与PSP病理区域重叠），模拟PSP中所见的胆碱能脚桥脑神经元的广泛损失，并产生独特的PSP样缺陷组合：惊吓反射，注意力和运动功能。本研究通过允许病变孵育超过一年来扩展了这些发现，并比较了脚桥脑胆碱能损伤和假损伤大鼠的行为和死后病理学。有早期惊吓反射缺陷，未随时间改善。在这一年中，运动功能逐渐下降，包括在导航各种光束时“滑倒”的次数增加，以及从高架平台到家庭的协调性差。组织学分析发现，胆碱能脚桥脑神经元的损失导致黑质酪氨酸羟化酶阳性神经元的显著损失和侧脑室的显著扩大。后者是PSP和PD之间的区别特征。这种PSP的临床前动物模型有可能进一步加深我们对PSP的理解，并有助于测试潜在的治疗药物。
Progressive supranuclear palsy (PSP) is the most common atypical Parkinsonism. Although PSP shares some symptomology with Parkinson's disease (PD), PSP has a different underlying pathology characterized by tau aggregation. Furthermore, PSP sufferers respond poorly to PD medications and there are no effective alternative therapeutics. The development of both palliative and disease altering therapeutics has been hampered by the lack of an animal model that displays relevant PSP‐like pathology and behavioral deficits. Previously, our lab found that in rats the selective removal of cholinergic pedunculopontine neurons (whose axonal projections overlap with areas of PSP pathology), mimics the extensive loss of cholinergic pedunculopontine neurons seen in PSP, and produces a unique PSP‐like combination of deficits in: startle reflex, attention, and motor function. The present study extends those findings by allowing the lesion to incubate for over a year and compares behavioral and post‐mortem pathology of pedunculopontine‐cholinergic‐lesioned and sham‐lesioned rats. There was an early startle reflex deficit which did not improve over time. Progressive declines in motor function developed over the course of the year, including an increase in the number of “slips” while navigating various beams and poorly coordinated transitions from an elevated platform into homecages. Histological analysis discovered that the loss off cholinergic pedunculopontine neurons precipitated a significant loss of substantia nigra tyrosine hydroxylase‐positive neurons and a significant enlargement of the lateral ventricles. The latter is a distinguishing feature between PSP and PD. This preclinical animal model of PSP has the potential to further our understanding of PSP and aid in the testing of potential therapeutic agents.