Different Dopaminergic Dysfunctions Underlying Parkinsonian Akinesia and Tremor
Different Dopaminergic Dysfunctions Underlying Parkinsonian Akinesia and Tremor
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DOI：
10.3389/fnins.2019.00550
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发表时间：
2019-05-29
影响因子：
4.3
通讯作者：
Baldassarre, Gianluca
中科院分区：
文献类型：
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作者：
Caligiore, Daniele;Mannella, Francesco;Baldassarre, Gianluca
尽管帕金森病运动不能和震颤的发生传统上与多巴胺能变性有关，但导致这些损伤的多方面神经过程尚不完全清楚。因此，目前的多巴胺药物无法针对患者的特定功能障碍进行调整，导致仿制药疗法对运动不能和震颤产生不同的效果。本文提出了一种计算模型，重点关注多巴胺损伤在运动不能和静止性震颤发生中的作用。该模型具有三个关键特征，迄今为止从未集成到单个计算系统中：（a）基于基底神经节-丘脑-皮质环路的相关已知系统级解剖学约束的架构； (b) 具有生理学限制参数的尖峰神经元； (c) 阶段性和强直性多巴胺释放效果的详细模拟。该模型表现出的神经动力学与灵长类动物和人类大脑中记录的神经动力学一致。此外，它表明运动不能可能涉及强直性和阶段性多巴胺失调，而静息性震颤可能主要是由强直性多巴胺释放和多巴胺受体反应性损伤引起的。这些结果可能会导致基于帕金森病的系统级观点并以不同的方式针对阶段性和强直性多巴胺开发新疗法。
Although the occurrence of Parkinsonian akinesia and tremor is traditionally associated to dopaminergic degeneration, the multifaceted neural processes that cause these impairments are not fully understood. As a consequence, current dopamine medications cannot be tailored to the specific dysfunctions of patients with the result that generic drug therapies produce different effects on akinesia and tremor. This article proposes a computational model focusing on the role of dopamine impairments in the occurrence of akinesia and resting tremor. The model has three key features, to date never integrated in a single computational system: (a) an architecture constrained on the basis of the relevant known system-level anatomy of the basal ganglia-thalamo-cortical loops; (b) spiking neurons with physiologically-constrained parameters; (c) a detailed simulation of the effects of both phasic and tonic dopamine release. The model exhibits a neural dynamics compatible with that recorded in the brain of primates and humans. Moreover, it suggests that akinesia might involve both tonic and phasic dopamine dysregulations whereas resting tremor might be primarily caused by impairments involving tonic dopamine release and the responsiveness of dopamine receptors. These results could lead to develop new therapies based on a system-level view of the Parkinson's disease and targeting phasic and tonic dopamine in differential ways.