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

摘要：在肌萎缩侧索硬化症（ALS）患者及相关运动神经元中， 神经元疾病（MND）原发性侧索硬化症（PLS），运动控制缺陷的发生作为一个后果 皮质脊髓神经元（CSN）的退化。ALS比PLS更常见，遗传学上， 更复杂的是，与超过30个ALS相关基因的因果突变相关的家族形式。在 然而，这些ALS小鼠的CSN的功能障碍和变性尚未被仔细检查， 并且在ALS的这些模型系统中涉及皮质脊髓（CS）回路的数据令人惊讶地有限。 其中一个原因可能是CSN和脊髓MN之间的连接模式非常不同， 人类对老鼠在人类中，位于腹索和侧索的CS轴突形成直接的 与MN（皮质-运动神经元（CM）连接）和中间神经元的连接。与此相反的是， 小鼠的CS轴突主要位于背索中，并且仅与 MN通过前运动中间神经元。因此，我们将使用具有CM的丛蛋白A1突变小鼠， 连接与ALS小鼠模型一起分析CS电路。我们的核心假设是， ALS小鼠中CS电路的进行性缺陷将因CM的建立而加剧 连接.在目标1中，我们将确定CM在ALS小鼠模型中CS回路的形成 连接.目的2：利用CM技术，研究ALS小鼠模型中CS回路的功能 连接.在目标3中，我们将检查具有CM连接的ALS小鼠模型中的熟练动作。 这些研究将为ALS/PLS中CS变性机制的研究提供模型系统， 以测试针对这些疾病中的上运动神经元功能障碍的新疗法。

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.