Cellular and Circuit Mechanisms of Upper Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis (ALS)

肌萎缩侧索硬化症 (ALS) 上运动神经元变性的细胞和电路机制

• 批准号: 326014787
• 负责人: Professorin Dr. Sabine Liebscher
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326014787?language=en
• 关键词: Cellular; Circuit; Mechanisms; Upper; Motor

The degeneration of upper motor neurons (UMN) represents a cardinal feature of Amyotrophic Lateral Sclerosis (ALS), a devastating disease that is characterized by the joint impairment of upper and lower motor neurons (LMN) in cortex and spinal cord, respectively. However, research in the past has strongly focused on the study of lower motor neuron impairment, while little is known about the mechanisms governing UMN dysfunction. Recent findings suggest that UMNs are affected very early in the disease and that their dysfunction precedes the degeneration of LMN. One key characteristic, not only prominent in ALS, but also in other neurodegenerative diseases, are changes in intrinsic excitability. These are reported in prodromal stages of the disease as hyperexcitability, caused by a dysbalance between excitation and inhibition, which notably can affect cell types other than the actual prime target of the respective neurodegenerative disease in a hitherto unknown sequence. Understanding how different components of neural circuits are compromised in the course of the disease is, thus important in order to identify new therapeutic targets. This proposal is aimed at investigating key functional units within the motor cortex microcircuit in ALS mouse models to unravel new aspects of the cortical pathology in the disease that ultimately lead to UMN degeneration. These encompass structural and functional alterations of not only UMN, but also upstream cells in cortical layer II/III driving UMN, as well as intratelencephalic neurons, such as corticostriatal neurons, providing intralaminar input and multiple classes of interconnected interneurons regulating activity within an area. Moreover, non-cell autonomous processes, conveyed by microglia and astrocytes, were suggested to play an important role in ALS pathogenesis. As both are strongly involved in the regulation of circuits, their dysfunction likely has a major impact on neuronal health. I will employ state-of-the-art in vivo two-photon imaging in awake mice combined with molecular approaches to selectively record from defined cell populations, such as inhibitory subtypes, UMNs or layer II/III cells, to monitor and correlate structural and functional alterations of neurons and glia cells throughout the course of the disease. This approach should enable me to capture early changes of neuronal dysfunction, such as synapse instability, and to address its impact on the neuron s fate, by characterizing their consequences on neuronal response properties. Moreover, I will assess whether structural and functional alterations hinge on molecular changes, such as increased intracell. calcium, the formation of intracell. aggregates or signs of apoptosis. I believe that with these studies I can elucidate a sequence of events occurring within M1 circuits that governs the degeneration of UMN and which hopefully helps identifying new therapeutic strategies.

肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis，ALS）是一种以皮层和脊髓上、下运动神经元（upper and lower motor neurons，LMN）联合损害为特征的严重疾病，其主要特征是上运动神经元（upper motor neurons，UMN）变性。然而，过去的研究主要集中在下运动神经元损伤的研究，而对UMN功能障碍的机制知之甚少。最近的研究结果表明，UMN在疾病的早期就受到影响，并且它们的功能障碍先于LMN的变性。一个关键特征，不仅在ALS中突出，而且在其他神经退行性疾病中也是如此，是内在兴奋性的变化。这些在疾病的前驱期被报道为由兴奋和抑制之间的失衡引起的过度兴奋，其可以以迄今未知的顺序显著地影响除了相应神经退行性疾病的实际主要靶标之外的细胞类型。因此，了解神经回路的不同组成部分在疾病过程中如何受损对于确定新的治疗靶点非常重要。该提案旨在研究ALS小鼠模型中运动皮层微电路内的关键功能单元，以揭示最终导致UMN变性的疾病中皮层病理学的新方面。这些包括结构和功能的改变，不仅UMN，而且在皮质层II/III驱动UMN的上游细胞，以及端脑内神经元，如皮质纹状体神经元，提供intralaminar输入和多个类别的相互连接的中间神经元调节活动的区域内。此外，由小胶质细胞和星形胶质细胞传递的非细胞自主过程被认为在ALS发病机制中起重要作用。由于两者都强烈参与电路的调节，它们的功能障碍可能对神经元健康产生重大影响。我将在清醒小鼠中采用最先进的体内双光子成像，结合分子方法选择性地记录定义的细胞群，如抑制亚型，UMN或II/III层细胞，以监测和关联整个疾病过程中神经元和神经胶质细胞的结构和功能变化。这种方法应该使我能够捕捉神经元功能障碍的早期变化，如突触不稳定性，并解决其对神经元命运的影响，通过表征它们对神经元反应特性的影响。此外，我将评估结构和功能的改变是否取决于分子变化，如细胞内的增加。钙，细胞内的形成。细胞凋亡的聚集或迹象。我相信，通过这些研究，我可以阐明M1回路中发生的一系列事件，这些事件控制着UMN的退化，并有望帮助确定新的治疗策略。