Corticospinal neuron dysfunction and degeneration in ALS: testing the role of corticomotor connectivity in motor neuron disease

ALS 中的皮质脊髓神经元功能障碍和变性：测试皮质运动连接在运动神经元疾病中的作用

• 批准号: 10523057
• 负责人: Neil Alan Shneider
• 金额: $ 68.19万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523057
• 关键词: ALS patients; Address; Adult; Affect; Amyotrophic Lateral Sclerosis; Anatomy; Animal Experiments; Animal Model; Axon; Behavioral Assay; Biological Models; Clinical; Complex; Data; Defect; Disease; Disease Progression; Dorsal; Electromyography; Electrophysiology (science); Functional disorder; Genes; Human; Impairment; Interneurons; Label; Lateral; Link; Maintenance; Manuals; Modeling; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Motor Skills; Movement; Mus; Muscle denervation procedure; Mutant Strains Mice; Mutation; Nerve Degeneration; Neuroanatomy; Neuronal Dysfunction; Neurons; Pathogenesis; Pathology; Patients; Pattern; Phenotype; Predisposition; Primary Lateral Sclerosis; Regional Anatomy; Research; Role; Signal Transduction; Signs and Symptoms; Spinal; Synapses; Testing; Vertebral column; Viral; advanced disease; causal variant; dexterity; disease phenotype; grasp; improved; in vivo; mad itch virus; microstimulation; motor behavior; motor control; mouse model; neuropathology; new therapeutic target; novel; novel therapeutics; postnatal; public health relevance; skills; superoxide dismutase 1

Abstract (Summary): In patients with amyotrophic lateral sclerosis (ALS) and the related motor neuron disease (MND) primary lateral sclerosis (PLS), deficits in motor control occur as a consequence of the degeneration of corticospinal neurons (CSNs). ALS is more common than PLS, and genetically more complex, with familial forms associated with causal mutations in over 30 ALS-related genes. In these ALS mice, however, dysfunction and degeneration of CSNs have not been carefully examined, and data implicating corticospinal (CS) circuits in these model systems of ALS is surprisingly limited. One reason for this may be the very different pattern of connectivity between CSNs and spinal MNs in humans vs. mice. In humans, CS axons located in the ventral and lateral funiculi form direct connections with both MNs (cortico-motoneuronal (CM) connections) and interneurons. In contrast, CS axons in mice are located mainly in the dorsal funiculus and only form indirect connections with MNs through pre-motor interneurons. Therefore, we will use PlexinA1 mutant mice which have CM connections together with ALS mouse models to analyze CS circuits. Our central hypothesis is that progressive defects in CS circuitry in ALS mice will be exacerbated by the establishment of CM connections. In Aim 1, we will determine formation of CS circuits in ALS mouse models with CM connections. In Aim 2, we will determine function of CS circuits in ALS mouse models with CM connections. In Aim 3, we will examine skilled movements in ALS mouse models with CM connections. These studies will provide a model system to study mechanisms of CS degeneration in ALS/PLS, and to test novel therapeutics targeting upper motor neuron dysfunction in these disorders.

摘要（摘要）：肌萎缩性侧硬化症患者（ALS）和相关电动机 神经元疾病（MND）原发性硬化症（PLS），导致运动控制的缺陷是结果 皮质脊髓神经元（CSN）的变性。 ALS比PL更常见，并且在遗传上 更复杂的是与30多个与ALS相关基因的因果突变有关的家族形式。在 但是，这些ALS小鼠的功能障碍和CSN的变性尚未仔细检查， 与这些ALS模型系统中皮质脊髓（CS）电路有关的数据非常有限。 原因之一可能是CSN和脊柱MN之间的连通性模式非常不同 人类与老鼠。在人类中，位于腹侧和外侧funiculi的CS轴突直接 与MNS（Cortico-Motoneranal（CM）连接）和中间神经元的连接。相比之下， 小鼠中的CS轴突主要位于背侧曲目，仅形成间接连接 MN通过运动前中间神经元。因此，我们将使用具有CM的Plexina1突变小鼠 连接与ALS小鼠模型一起分析CS电路。我们的中心假设是 CM的建立将使ALS小鼠CS电路的渐进缺陷加剧 连接。在AIM 1中，我们将确定具有CM的ALS小鼠模型中CS电路的形成 连接。在AIM 2中，我们将确定具有CM的ALS小鼠模型中CS电路的功能 连接。在AIM 3中，我们将检查具有CM连接的ALS鼠标模型中的熟练运动。 这些研究将为研究ALS/PL的CS变性机理提供模型系统，以及 测试针对这些疾病中上运动神经元功能障碍的新型治疗剂。