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

摘要(综述)：肌萎缩侧索硬化症(ALS)及其相关运动 神经元病(MND)、原发性侧索硬化症(PLS)、运动控制缺陷 皮质脊髓神经元(CSNS)变性。肌萎缩侧索硬化症比偏头痛更常见，而且在基因上 更为复杂，家族性形式与30多个ALS相关基因的因果突变有关。在……里面 然而，这些ALS小鼠的CSNS功能障碍和退化没有得到仔细的检查， 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 人类与老鼠的较量。在人类，位于腹侧和外侧穹隆的CS轴突直接形成 与MNS(皮质运动神经元(CM)连接)和中间神经元的连接。相比之下， 小鼠CS轴突主要位于背索，仅与 MNS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 结合ALS小鼠模型分析CS电路。我们的中心假设是 CM的建立将加剧ALS小鼠CS回路的进行性缺陷 关系。在目标1中，我们将确定在肌萎缩侧索硬化症小鼠模型中CS回路的形成 关系。在目标2中，我们将用CM确定ALS小鼠模型中CS回路的功能 关系。在目标3中，我们将研究肌萎缩侧索硬化症小鼠模型的熟练动作。 这些研究将为研究肌萎缩侧索硬化症/肌萎缩侧索硬化症的退变机制提供一个模型系统。 测试针对这些疾病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.