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.

项目摘要 虽然帕金森氏病（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 DA能）神经元1 -3，出现和 基底神经节回路的升级和运动功能障碍仍然定义不清。SN DA能的变性 在PD 4 -6中，神经元的表达早于症状的表达。在诊断时，约50-75%的黑质纹状体 DA能轴突和~30%的SN DA能神经元不再表达DA细胞标志物或已丢失7，8， 广泛的前驱期，被代偿机制掩盖9 -25。随着退化的进行， 间接途径中的活性日益失调24，26-41和适应不良可塑性13 -24可能 基底神经节计算能力逐渐退化，导致运动缺陷17，18，26- 28，36 -40。该电路 病理生理学也被认为是SN DA能神经元中生物能量应激的额外来源 这可能会加速它们的退化42 -47。虽然这些概念似乎是合理的，但在科学研究中无法严格研究。 急性毒素模型，模拟晚期PD中DA的缺乏，但不是DA能神经元的时空模式。 患者的神经元变性48，49.为了填补这一空白，我们建议检查帕金森症的出现， 其在PD 50的MitoPark模型中间接途径功能的影响。MitoPark小鼠是通过 DA能神经元中核编码线粒体转录因子TFAM的遗传缺失， 导致线粒体功能障碍50 -52，这些细胞在家族性和散发性的 PD53-58这些小鼠概括了PD的关键方面，包括：1）进行性SN DA能神经元变性 和左旋多巴敏感的运动缺陷，但在一个压缩的，实验上易于处理的时间范围内，跨越6- 7个月50，51，59; 2）在最初的研究中，背侧纹状体中SN DA能神经元轴突终末的相对敏感性 帕金森病的分期50，52，59-61; 3）SN与腹侧被盖区DA能的相对易感性 神经元50，51，59; 4）回路可塑性和病理生理学类似于晚期PD及其模型（试点 数据）。使用体内和离体电生理学、光遗传学、化学遗传学、双光子成像， 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 前驱期MitoPark小鼠间接通路和运动功能保留的机制; 2)确定有症状的进行性间接通路和运动功能障碍的潜在机制， MitoPark小鼠; 3）确定运动功能障碍和SN DA能神经元的变性是否可以被抑制。 在症状性MitoPark小鼠中通过化学遗传学操纵间接途径活性而被拯救。通过 执行这项研究，我们将了解为什么基底神经节间接通路功能的各个方面最初是 对SN DA能神经元变性有弹性但最终失调，以及是否是化学遗传性的 间接途径操作是帕金森综合征的有效的对症和/或疾病改善疗法。