Laboratory for Experimental Neuroregeneration, Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany.
Laboratory for Experimental Neurorehabilitation, Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany.
PLoS One. 2023 Oct 31;18(10):e0291740. doi: 10.1371/journal.pone.0291740. eCollection 2023.
Locomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of individual spinal interneuron (SpIN) subtypes, the phenotype of combined SpIN loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VIII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system that strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VIII in spinal L2-L4 correlates with hindlimb dysfunction. White matter alterations and lower motoneuron loss were not observed with this KA lesion. Animals did not regain lost sensorimotor function three months after injury, indicating that natural recovery mechanisms of the spinal cord cannot compensate for loss of laminae V-VIII neurons. As gray matter damage accounts for neurological/walking dysfunction in instances of spinal cord injury affecting the cervical or lumbar enlargement, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function.
运动是一项复杂的任务，涉及脊髓灰质中的兴奋和抑制回路。虽然基因敲除研究检查了单个脊髓中间神经元（SpIN）亚型的功能，但组合 SpIN 缺失的表型仍有待探索。我们修改了一种海人酸损伤，以损伤雌性大鼠腰骶部脊髓扩大（脊髓 L2-L4）的中间灰质（层 V-VIII）。彻底的、定制的行为评估显示，在损伤后两周，大鼠的后肢功能、精细行走、协调、平衡和步态都存在缺陷。我们使用随机森林算法，将这些行为评估组合成一个高度预测性的二进制分类系统，与头尾部轴突的结构缺陷有很强的相关性。机器学习定量证实，脊髓 L2-L4 的层 V-VIII 的中间神经元损伤与后肢功能障碍相关。用这种 KA 损伤没有观察到白质改变和较低的运动神经元丢失。动物在损伤后三个月没有恢复失去的感觉运动功能，这表明脊髓的自然恢复机制不能补偿层 V-VIII 神经元的丢失。由于灰质损伤在影响颈段或腰段脊髓扩大的脊髓损伤中导致神经/行走功能障碍，因此这项研究为新的神经再生疗法奠定了基础，以替代这些对感觉运动功能至关重要的丢失神经元池。
