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 帕金森氏病（PD）的头肾上腺素和偶然症状显然与退化有关 黑质nigra多巴胺能（Sn Daergic）神经元1-3，这是出现和 巴萨神经节电路和运动功能障碍的升级仍然很差。 sn daergic的变性 长期以来，神经元在PD4-6中的症状表达之前。在诊断时约50-75％ Daergic轴突和〜30％的SN Daergic神经元不再表达DA细胞标记或丢失了17,8 在广泛的前驱时期，由补偿机制9-25掩盖。随着变性的进行， 越来越失调的活性24,26-41和不良适应性可塑性13-24在间接途径中可能 逐渐降解基本的神经节计算，导致电动机定义17,18,26-28,36-40。这个电路 还建议病理生理学作为SN Daergic神经元中生物能胁迫的附加来源 这可能会加速其退化42-47。尽管是合理的，但这些概念不能严格研究 急性毒素模型，这些模型模仿了晚期PD中不存在DA的急性毒素模型，但不是daergic的时空模式 患者的神经元变性为48,49。为了填补这一空白，我们建议研究帕金森主义的出现和 它在PD50的Mitopark模型中间接途径函数的影响。 Mitopark小鼠是通过 核编码的线粒体转录因子TFAM的遗传缺失在Daergic神经元中，该因子 导致线粒体功能障碍50-52，这些细胞以家族性和零星形式的一致脆弱性 PD53-58。这些小鼠概括了PD的关键方面，包括：1）渐进性SN DAERAGIC神经元变性 左旋多巴敏感的电动机定义了，但在跨越6--的压缩，可拖动的时间范围内 7个月50,51,59; 2）Sn Daeragic神经元轴突末端的相对敏感性在初始纹状体中 帕金森氏症的阶段50,52,59-61; 3）SN与腹侧对接区域Daergic的相对敏感性 神经元50,51,59; 4）电路塑性和病理生理类似于高级PD及其模型（飞行员） 数据）。使用体内和体内电生理，光遗传学，化学遗传学，2光子成像， 电化学，免疫组织化学和行为方法，我们提出了3个具体目的：1）确定 负责在前驱Mitopark小鼠中保持间接途径和运动功能的机制； 2）确定有症状的渐进性间接途径和运动功能障碍的机制 Mitopark小鼠； 3）确定运动功能障碍和SN Daergic神经元的变性是否可以是 通过化学上操纵间接途径活性在有症状的Mitopark小鼠中救出。通过 执行这项研究，我们将了解为什么最初是基底神经节间接途径功能的方面 SN Daergic神经元的变性以及化学遗传学是否有弹性，但最终因失调而失调 间接途径操纵是帕金森氏症的有效症状和/或疾病修改的疗法。