The role of inhibition in the control of locomotion

从原始的原始脊椎动物到人类，脊髓中包含的神经回路可以产生各种物种的基本运动模式。虽然某些脊椎动物（如七鳃鳗和爪蟾）的功能架构是众所周知的，但对哺乳动物CPGs的了解要少得多。开始变得清楚的是，每个半节内的相互兴奋的中间神经元可以形成内核或单位振荡器，该内核或单位振荡器与位于同侧不同节段或另一半节中的其他振荡器互连。因此，抑制驱动是至关重要的，允许一个完整的剧目的运动行为的起源。然而，我们仍然没有完全掌握抑制在创造节奏中的作用。这部分是因为我们缺乏在节段水平上完全操纵抑制性驱力的能力。 在这个提议中，我们将使用光遗传学方法在完整和脊髓损伤的小鼠中在节段水平上操纵抑制驱动。与药理学方法相比，这种方法提供了三个关键优势：（1）我们可以快速增加或减少抑制性中间神经元中的尖峰活动，因为光诱发的反应很快;（2）我们可以将光的递送定位到单个节段;（3）我们可以调节抑制的强度。这使我们能够在步骤周期的定义阶段修改抑制强度，这是传统药理学策略无法做到的。 总之，我们的计划旨在加强对控制行走的神经回路的理解，并在长期内产生治疗脊髓损伤的新方法。

The spinal cord contains neural circuits that can generate the basic locomotor pattern in a variety of species from primitive protovertebrates to man. While the functional architecture is well known for certain vertebrates such as lamprey and xenopus, much less is known about mammalian CPGs. What is starting to become clear is that the mutually excitatory interneurons within each hemisegment may form the kernel or unit oscillator which is interconnected with other oscillators located ipsilaterally in different segments or in the other hemisegment. Thus inhibitory drive is crucial to allow the genesis of a full repertoire of locomotor behaviors. However, we still don't have a full grasp on the role of inhibition in crafting the rhythm. Partly this is because we lack the ability to fully manipulate inhibitory drive at a segmental level. In this proposal we will use optogenetic approaches to manipulate inhibitory drive at a segmental level in both intact and spinally injured mice. This approach offers three key advantages over pharmacological approaches: (1) we can increase or decrease spiking activity in inhibitory interneurons quickly since the light evoked responses are fast (2) we can localize the delivery of light to a single segment and (3) we can modulate the strength of inhibition. This allows us to modify the strength of inhibition at defined phases of the step cycle, something that was impossible to do with traditional pharmacological strategies. In summary our program is designed to enhance understanding of the neural circuits that control walking and over the long-term generate new approaches to treating spinal cord injuries.