NOVEL EXPERIMENTAL PLATFORM FOR PRODOMAL PARKINSON'S DISEASE

 描述(由申请人提供)：帕金森病(PD)是一种运动障碍，其显著的运动症状是由于纹状体失去多巴胺能神经支配而引起的。运动症状包括运动速度减慢、协调性降低和步态异常。这些症状通常不会出现，直到纹状体中的多巴胺水平降低了70%-80%。在临床上，这意味着那些在运动症状开始时寻求医疗帮助的患者很可能多年来一直生活在长期低水平的多巴胺中。在疾病的早期阶段，多巴胺水平处于病理性的低水平，但运动症状尚未出现，这被称为前驱期，可能是进行治疗的最佳时期。然而，大多数研究利用帕金森氏症运动障碍的动物模型，仅在严重运动功能障碍已经发生后的耗竭的晚期阶段研究电路功能障碍。这些动物模型极大地提高了我们对大量多巴胺耗竭动物中存在的突触和电路水平变化的理解，但我们仍然对电路功能障碍的进展知之甚少，也就是导致运动障碍出现的代偿性可塑性，这一理解可能对于在疾病变得无法治愈之前阻止疾病的进展至关重要。这项拟议研究的主要目标是使用一种新的多巴胺耗竭范例来研究导致运动缺陷出现的回路功能障碍和代偿的进展，其中多巴胺损失的开始和进展可以被严格控制。在目标1中，我们将对在几周到几个月内逐渐耗尽的小鼠的大脑区域进行无偏见的高通量筛查，相对于急性耗尽的小鼠。在急性和逐渐耗尽的动物中，大脑区域表现出不同的活动，将识别潜在的代偿性可塑性部位，为未来研究前驱PD期间网络适应的细胞和突触机制提供基础。在目标2中，我们将通过比较逐渐耗尽的小鼠和已建立的帕金森病遗传模型Thy1-αSyn中观察到的大脑活动模式来验证我们的模型，其中约40%的多巴胺在14个月大时丢失。在两种模型中显示共同变化的大脑区域将揭示与疾病相关的可塑性最有希望的部位。最后，在目标3中，我们将使用尖端的电生理学方法来记录在我们的逐渐耗尽范例的持续时间内，候选脑区的神经活动。这些实验将确定导致运动缺陷出现的网络补偿的神经关联。综上所述，这些结果将为前驱PD过程中代偿性可塑性的定位和进展提供新的见解，并将为进一步研究疾病中适应性可塑性的细胞和突触基础奠定基础。

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a movement disorder whose hallmark motor symptoms arise due to loss of dopaminergic innervation of the striatum. Motor symptoms include slowed movement, decreased coordination, and gait abnormalities. These symptoms typically do not present until dopamine levels in the striatum have been reduced by 70-80%. Clinically, this means that patients who seek medical help at the onset of motor symptoms have likely been living with chronically low levels of dopamine for years. This early phase of the disease, when dopamine levels are pathologically low but motor symptoms have not yet presented, is called the prodromal phase, and is likely the optimal period in which to administer therapies. However, most research utilizing animal models of parkinsonian motor impairments investigates circuit dysfunction only in late stages of depletion, after severe motor dysfunction has already occurred. These animal models have greatly advanced our understanding of the synaptic and circuit-level changes present in massively dopamine depleted animals, but we still know very little about the progression of circuit dysfunction, or compensatory plasticity leading up to the appearance of motor impairments, an understanding that may be critical to halting disease progression before it becomes incurable. The primary goal of the proposed research is to study the progression of circuit dysfunction and compensation leading up to the appearance of motor deficits using a novel dopamine depletion paradigm where the onset and progression of dopamine loss can be tightly controlled. In Aim 1, we will conduct a nonbiased, high throughput screen for brain areas showing differential activation in mice gradually depleted over weeks to months, relative to acutely depleted mice. Brain areas showing differential activity in acutely vs. gradually depleted animals will identify potential sits of compensatory plasticity, providing a foundation for future studies of the cellular and synaptic mechanisms of network adaptations during prodromal PD. In Aim 2, we will validate our model by comparing patterns of brain activity in gradually depleted mice to those observed in an established genetic model of PD, Thy1-αSyn, where ~40% of dopamine is lost by age 14 months. Brain areas showing common changes across both models will reveal the most promising sites of disease-relevant plasticity. Finally, in Aim 3, we will use cutting-edge electrophysiological approaches to record neural activity in candidate brain areas over the duration of our gradual depletion paradigm. These experiments will identify neural correlates of network compensation leading up the appearance of motor deficits. Combined, these results will provide novel insights into the location and progression of compensatory plasticity during prodromal PD, and will lay the foundation for future studies of the cellular and synaptic basis of adaptive plasticity in disease.