Optimizing ultraflexible electrodes and integrated electronics for high-resolution, large-scale intraspinal recording and modulation

电生理学作为一种直接测量神经元功能的技术，是神经科学中的一项关键技术。对科学家来说，记录和刺激清醒行为动物大脑不同区域的神经元数量，将活动与行为联系起来，已经成为常规。然而，同样的电生理在行为动物的脊髓中表现良好是不可逾越的。因此，虽然脊髓是运动和感觉的关键部位，但从功能角度来看，由于缺乏测量和调节脊髓神经元功能的工具，脊髓在很大程度上仍然是一个“黑匣子”。对有行为的动物的脊髓进行电生理学研究的主要困难在于脊髓是非常灵活的，在行为过程中会移动和弯曲。几乎所有现有的神经电极，在机械上比脊髓组织更坚硬，不能跟随这种运动，因此产生过多的噪音和位置漂移，导致脊髓损伤或长期恐慌。在这里，我们提出了一套围绕超柔性电极的技术来解决这个挑战。我们现在有初步的数据证明这些探针可以从行为小鼠的脊髓神经元中获得高质量的单单元记录。显然，当动物以不同的行为活跃地移动时，我们仍然能够通过刺突分类稳定地跟踪神经元数量。我们的初步长期结果也证实了脊髓植入后5个多月的慢性体内记录。受到这一成功的激励，我们提出了优化脊髓研究技术的研究计划。至关重要的是，我们汇集了一群杰出的神经科学家与我们一起开发手术方法，并在不同的脊柱区域，动物模型和研究主题中测试设备。这些努力分为三个目标。我们希望这项新技术能够在脊髓介导的广泛行为（不同速度的运动、停止、反射撤回、伸手、抓握、排尿等）的背景下，为单个脊髓细胞的功能提供新的视角。这将使神经科学家能够将发达的脊髓细胞类型的遗传和发育特征与神经回路联系起来；了解神经系统的其他部分是如何与脊髓相互作用的。从转译的角度来看，这为通过慢性监测更好地了解脊髓损伤和疾病的病因和进展提供了机会；开辟了脊髓内接口治疗脊髓损伤、中风、运动障碍和运动神经元疾病的潜力。

Electrophysiology is a critical technology in neuroscience as a direct measure of neuronal functions. It has become routine for scientists to record and stimulate neuron populations in different brain regions in awake behaving animals, correlating activity with behavior. However, it has been insurmountable for the same electrophysiology to perform well in the spinal cord of behaving animals. For this reason, while the spinal cord is a critical site for locomotion and sensations, it remains largely a “black box” from a functional perspective, due to the lack of tools to measure and modulate spinal neurons while they are functioning. The main difficulty of doing electrophysiology in the spinal cord of behaving animals is because the cord is extremely mobile, moving and bending during behavior. Almost all existing neural electrodes, being mechanically more rigid than spinal tissues, fail to follow such movements, therefore yielding excessive noise and position drifts and lead to spinal injury or scaring in the long term. Here, we propose a suite of technologies centering around ultraflexible electrodes to address this challenge for the community. We now have preliminary data proving these probes achieved high quality single unit recording from spinal neurons of behaving mice. Markedly, when the animals are actively moving in diverse behaviors, we were still able to stably track neuron populations through spike sorting. Our preliminary long-term results also verified chronic in vivo recording for over 5 months after implantation in the spinal cord. Motivated by this success, we propose research plans to optimize this technology for spinal cord studies. Critically, we have brought together a group of outstanding neuroscientists to work with us in developing surgical approaches, and testing devices across different spinal areas, animal models, and research topics. These efforts are organized into three aims. We expect this new technology will enable new perspectives on the function of individual spinal cells in the context of a wide spectrum of behaviors that the spinal cord mediates (different speeds of locomotion, stopping, reflex withdrawal, reaching, grasping, urination, etc.). This will allow neuroscientists to connect the well-developed genetic and developmental characterization of spinal cell types to the circuit; to understand how other parts of the nervous system interact with the spinal cord. From a translational perspective, this offers the opportunity for a better understanding of the etiology and progression of spinal cord injury and disease by chronic monitoring; opens up the potential for intra-spinal interfaces that treat spinal cord injury, stroke, movement disorders, and motor neuron diseases.