Resilience, Dysregulation, and Rescue of Basal Ganglia Indirect Pathway Function in Progressive Parkinsonism

进行性帕金森病中基底神经节间接通路功能的弹性、失调和挽救

• 批准号: 10440048
• 负责人: Mark D Bevan
• 金额: $ 60.71万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440048
• 关键词: Acute; Axon; Basal Ganglia; Behavioral; Bioenergetics; Bradykinesia; Brain; Cells; Chronic; Cognitive deficits; Corpus striatum structure; Data; Diagnosis; Disease; Dorsal; Electrophysiology (science); Exhibits; Functional disorder; Genetic; Human; Image; Learning; Levodopa; Link; Masks; Membrane; Methods; Mitochondria; Modeling; Motor; Movement; Mus; Nerve Degeneration; Neurons; Nuclear; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pattern; Predisposition; Presynaptic Terminals; Property; Research; Residual state; Source; Stress; Substantia nigra structure; Symptoms; Synapses; Testing; Time; Toxin; Ventral Tegmental Area; brain abnormalities; dopaminergic neuron; in vivo; mitopark mouse; motor deficit; motor disorder; mouse model; optogenetics; prevent; resilience; spatiotemporal; transcription factor; transmission process; two-photon

Project Summary While the bradykinetic and akinetic symptoms of Parkinson’s disease (PD) are clearly linked to the degeneration of substantia nigra dopaminergic (SN DAergic) neurons1-3, the mechanisms that underlie the emergence and escalation of basal ganglia circuit and motor dysfunction remain poorly defined. Degeneration of SN DAergic neurons long precedes the expression of symptoms in PD4-6. At the point of diagnosis ~50-75% of nigrostriatal DAergic axons and ~30% of SN DAergic neurons no longer express DA cell markers or have been lost7,8, arguing for an extensive prodromal period, masked by compensatory mechanisms9-25. As degeneration proceeds, increasingly dysregulated activity24,26-41 and maladaptive plasticity13-24 within the indirect pathway may progressively degrade basal ganglia computation, leading to motor deficits17,18,26-28,36-40. This circuit pathophysiology has also been suggested as an additional source of bioenergetic stress in SN DAergic neurons that could accelerate their degeneration42-47. Although plausible, these concepts cannot be rigorously studied in acute toxin models that mimic the absence of DA in advanced PD but not the spatiotemporal pattern of DAergic neuron degeneration in patients48,49. To fill this gap, we propose to examine the emergence of parkinsonism and its impact of indirect pathway function in the MitoPark model of PD50. MitoPark mice are generated through genetic deletion of the nuclear encoded mitochondrial transcription factor TFAM in DAergic neurons, which causes mitochondrial dysfunction50-52, a consistent vulnerability of these cells in familial and sporadic forms of PD53-58. These mice recapitulate key aspects of PD, including: 1) progressive SN DAergic neuron degeneration and levodopa-sensitive motor deficits, but within a compressed, experimentally tractable time frame spanning 6- 7 months50,51,59; 2) relative susceptibility of SN DAergic neuron axon terminals in the dorsal striatum in the initial stages of parkinsonism50,52,59-61; 3) relative susceptibility of SN versus ventral tegmental area DAergic neurons50,51,59; 4) circuit plasticity and pathophysiology analogous to that in advanced PD and its models (pilot data). Using in vivo and ex vivo electrophysiological, optogenetic, chemogenetic, 2-photon imaging, electrochemical, immunohistochemical, and behavioral approaches, we propose 3 specific aims: 1) determine the mechanisms responsible for the retention of indirect pathway and motor function in prodromal MitoPark mice; 2) determine the mechanisms underlying progressive indirect pathway and motor dysfunction in symptomatic MitoPark mice; 3) determine whether motor dysfunction and degeneration of SN DAergic neurons can be rescued in symptomatic MitoPark mice by chemogenetically manipulating indirect pathway activity. Through the execution of this research, we will learn why aspects of basal ganglia indirect pathway function are initially resilient to but ultimately dysregulated by degeneration of SN DAergic neurons, and whether chemogenetic indirect pathway manipulation is an effective symptomatic and/or disease-modifying therapy for parkinsonism.

项目概要 虽然帕金森病 (PD) 的运动迟缓和运动不能症状明显与退化有关 黑质多巴胺能 (SN DAergic) 神经元 1-3 的出现和出现的机制 基底神经节回路的升级和运动功能障碍仍不清楚。 SN DAergic 的退化 神经元的表达早于 PD4-6 的症状。诊断时约 50-75% 的黑质纹状体 DAergic 轴突和约 30% 的 SN DAergic 神经元不再表达 DA 细胞标记或已丢失7,8，争论 一个广泛的前驱期，被补偿机制所掩盖9-25。随着退化的进行， 间接途径中日益失调的活动24,26-41和适应不良的可塑性13-24可能 逐渐降低基底神经节的计算能力，导致运动缺陷17,18,26-28,36-40。这个电路 病理生理学也被认为是 SN DAergic 神经元生物能量应激的另一个来源 这可能会加速它们的退化42-47。尽管看似合理，但这些概念无法在 模拟晚期 PD 中 DA 缺失的急性毒素模型，但不模拟 DAergic 的时空模式 患者神经元变性48,49。为了填补这一空白，我们建议研究帕金森病的出现和 其对 PD50 MitoPark 模型中间接通路功能的影响。 MitoPark 小鼠是通过生成的 DAergic 神经元中核编码的线粒体转录因子 TFAM 的基因缺失， 导致线粒体功能障碍50-52，这些细胞在家族性和散发性形式中始终存在脆弱性 PD53-58。这些小鼠概括了 PD 的关键方面，包括：1) 进行性 SN DAergic 神经元变性 和左旋多巴敏感的运动缺陷，但在压缩的、实验上易于处理的时间范围内跨越 6- 7个月50,51,59; 2)初始时背侧纹状体中SN DAergic神经元轴突末端的相对敏感性 帕金森病的各个阶段50,52,59-61； 3) SN 与腹侧被盖区 DAergic 的相对敏感性 神经元50,51,59; 4) 类似于高级 PD 及其模型的电路可塑性和病理生理学（试点 数据）。使用体内和离体电生理学、光遗传学、化学遗传学、2-光子成像， 通过电化学、免疫组织化学和行为方法，我们提出了 3 个具体目标：1) 确定 MitoPark 前驱小鼠中间接通路和运动功能保留的机制； 2）确定症状性进行性间接途径和运动功能障碍的潜在机制 MitoPark小鼠； 3) 确定SN DAergic神经元的运动功能障碍和变性是否可以 通过化学遗传学操纵间接途径活性，在有症状的 MitoPark 小鼠中得到拯救。通过 执行这项研究，我们将了解为什么基底节间接通路功能的各个方面最初是 SN DAergic 神经元的退化具有弹性，但最终失调，以及是否化学遗传学 间接通路操纵是帕金森病的有效对症和/或疾病缓解疗法。