Dissecting Connectivity and Function of Transplanted Interneurons in the Injured Spinal Cord

颈髓损伤会导致手功能的立即和永久性丧失，原因是 神经回路中断。目前还没有有效的治疗方法可以改善神经预后。 适用于患有脊髓损伤(SCI)的个人。通过移植可以为损伤部位提供新的神经元 神经前体细胞(NPC)。这些细胞分化成不同亚型的神经元，支持 与受损宿主神经系统的神经元建立新的突触连接。多项研究 在临床前颈椎脊髓损伤模型中，报道了鼻咽癌移植后前肢功能的适度改善； 然而，移植神经元促进功能恢复的潜在机制尚不清楚。在……里面 为了开发更有效的神经替代策略，可以稳健地和可重复地改进 对于手功能的恢复，关键是要从根本上理解移植的神经元是如何 在突触和功能上整合到受损的前肢运动神经回路。为了解决这一知识差距，我们 将利用脊髓损伤的小鼠模型来表征NPC移植物对前肢功能恢复的贡献。 首先，我们将确定不同的移植神经元表型如何影响移植物突触整合。 进入受伤的神经系统。我们已经证明，鼻咽癌移植物可以丰富不同类别的神经元。 我们将使用这一策略来确定如何操纵移植物细胞成分影响与 马达电路受损。其次，我们将确定移植神经元的活性是否足以在功能上 调制前肢马达电路。通过对移植神经元的化学发生调节，我们将询问 移植物活性对前肢肌电生理反应的功能贡献。我们会 还要确定移植物活动是否是执行熟练的前肢运动功能所迫切需要的。 最后，我们将研究基于活动的康复是否可以增加移植物在 前肢运动回路，促进运动功能恢复。这项研究将建立一个新的和关键的 移植神经元整合到受损前肢并对其进行功能调节的能力框架 马达电路。此外，这项工作将突出移植物细胞组成在修复中的关键重要性。 功能结果。我们对鼻咽癌移植物进行功能性审问的策略适用于更广泛的工作 专注于恢复脊髓损伤后的运动或自主神经结果。这项研究的结果将揭示 神经移植可以提供治疗益处的新的生物学机制。这些发现将构成 一个关键的知识体系，将加快研究努力，开发出更有效的治疗人类 用于临床治疗脊髓损伤的细胞。

Injury to the cervical spinal cord results in an immediate and permanent loss of hand function due to massive disruption of neural circuitry. There are currently no effective therapies that can improve neurological outcomes for individuals living with spinal cord injury (SCI). New neurons can be provided to injury sites via transplantation of neural progenitor cells (NPCs). These cells differentiate into diverse subtypes of neurons that support the establishment of new synaptic connections with neurons in the injured host nervous system. Multiple studies have reported modest gains in forelimb function following NPC transplantation in preclinical cervical SCI models; however, the underlying mechanisms by which engrafted neurons promote functional recovery are unclear. In order to develop more effective neural replacement strategies that can robustly and reproducibly improve recovery of hand function, it is critical to develop a fundamental understanding of how engrafted neurons synaptically and functionally integrate into injured forelimb motor circuitry. To address this gap in knowledge, we will utilize a mouse model of SCI to characterize the contributions of NPC grafts to forelimb functional recovery. First, we will determine how varying the phenotypes of transplanted neurons influences graft synaptic integration into the injured nervous system. We have shown that NPC grafts can be enriched for distinct classes of neurons. We will use this strategy to determine how manipulating graft cellular composition influences integration with injured motor circuits. Second, we will determine whether graft neuron activity is sufficient to functionally modulate forelimb motor circuits. Through chemogenetic modulation of engrafted neurons, we will interrogate the functional contributions of graft activity to electrophysiological responses in the forelimb muscles. We will also determine whether graft activity is acutely required for the execution of skilled forelimb motor function. Finally, we will examine whether activity-based rehabilitation can increase synaptic integration of grafts into forelimb motor circuits and improve motor functional recovery. This study will establish a new and critical framework regarding the ability of engrafted neurons to integrate into and functionally modulate injured forelimb motor circuitry. Moreover, this work will highlight the critical importance of graft cellular composition in restoring functional outcomes. Our strategy to functionally interrogate NPC grafts has applications for broader work focused on restoring locomotor or autonomic outcomes after spinal cord injury. Results of this study will reveal new biological mechanisms by which neural grafts can provide therapeutic benefits. These findings will constitute a critical body of knowledge that will accelerate research efforts to develop more therapeutically effective human cells for clinical treatment of spinal cord injury.