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 而帕金森氏病(PD)的运动迟缓和运动迟缓症状显然与退行性变有关 黑质多巴胺能(SN-DA)神经元1-3的形成和形成机制 基底节环路的升级和运动功能障碍仍然不清楚。黑质能神经元退行性变 在PD4-6中，神经元早于症状的表达。确诊时约50-75%的黑质纹状体 DA能轴突和约30%的SN DA能神经元不再表达DA细胞标记或已丢失7，8，争论 广泛的前驱期，被补偿机制掩盖9-25。随着退化的进行， 间接途径内日益失调的活动24、26-41和适应不良的可塑性13-24可能 逐渐退化的基底节计算，导致运动缺陷17，18，26-28，36-40。这条线路 病理生理学也被认为是黑质DAR能神经元生物能量应激的另一个来源 这可能会加速它们42-47的退化。尽管这些概念看似合理，但不能在 模拟进展期帕金森病患者DA缺失但不是DA能时空模式的急性毒素模型 48，49例患者出现神经元变性。为了填补这一空白，我们建议研究帕金森症的出现和 其间接通路功能在PD50的MitoPark模型中的影响。MitoPark小鼠是通过 核编码线粒体转录因子TFAM在DAR能神经元中的遗传缺失 导致线粒体功能障碍50-52，这些细胞在家族性和散发性形式的 PD53-58。这些小鼠概括了帕金森病的关键方面，包括：1)进行性黑质DA能神经元变性 和左旋多巴敏感的运动缺陷，但在压缩的，实验上可以处理的时间范围内，跨越6- 7个月龄50，51，59；2)背侧纹状体SN能神经元轴突终末的相对易感性 帕金森病50、52、59-61期；3)黑质相对腹侧被盖区相对易感性 神经元50，51，59；4)类似于高级帕金森病及其模型(Pilot)的电路可塑性和病理生理学 数据)。使用体内和体外电生理、光发生、化学发生、双光子成像， 电化学、免疫组织化学和行为学方法，我们提出了三个具体目标：1)确定 前驱性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机制 MitoPark小鼠；3)确定运动功能障碍和黑质DA能神经元变性是否可以 通过化学遗传学操作间接途径活性在有症状的MitoPark小鼠中获救。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某些方面最初是 对黑质多巴胺能神经元的变性有弹性，但最终是失调的，以及是否发生了化学作用 间接通路操作是治疗帕金森氏症的一种有效的症状和/或疾病修正疗法。