Presynaptic Partners of Corticospinal Neurons to Control Skilled Movements

在运动行为过程中，高度协调的肌肉激活序列是 直接通过腹侧脊髓中运动神经元的微调放电来实现。这些电机 神经元主要由存在于所有哺乳动物中的脊髓中间神经元调节，脊髓中间神经元又连接到 其他脊髓神经元以及来自大脑的各种类型的下行神经元 (CS)神经元（CSNs）。位于运动皮层的CSNs连接脊髓中间神经元以控制运动 神经元活动，从而协调屈肌和伸肌肢体肌肉的活动，以控制 熟练的动作。虽然我们和其他人主要关注CSN通过轴突的输出， 也通过树突接受突触前神经元的输入。然而，识别和 对CSN的突触前神经元（pre-CSN）的功能的理解仍然有限。我们开发 狂犬病病毒为基础的检测，以确定前CSN。我们假设每个前CSN群体将是 明显激活以控制熟练运动和肌肉激活的离散阶段。来测试我们 假设，在目标1中，我们将映射大脑中CSN的突触前伴侣。我们将进一步确定 这些连接是功能性的（目标2）。最后，我们将确定前CSNs如何控制前肢熟练 运动和肌肉活动（目标3）。这些结果将提供必要的框架，不仅 定义脊髓运动回路，以及随后开发新的靶向干预措施，以治疗运动 残疾。

The highly orchestrated muscle activation sequences during motor behaviors are achieved directly through the fine-tuned firing of motor neurons in the ventral spinal cord. These motor neurons are mainly regulated by spinal interneurons present in all mammals, which are, in turn, connected to other spinal neurons as well as various types of descending neurons from the brain including corticospinal (CS) neurons (CSNs). CSNs located in the motor cortex connect to spinal interneurons to control motor neuron activity in all species, and thereby coordinate the activity of flexor and extensor limb muscles to control skilled movements. Although we and others mainly focused on outputs of CSNs through their axons, CSNs also receive inputs from their presynaptic neurons through their dendrites. However, the identification and understanding of the function of presynaptic neurons of CSNs (pre-CSNs) remains limited. We developed rabies virus-based assays to identify pre-CSNs. We hypothesize that each population of pre-CSNs will be distinctly activated to control discrete phases of skilled movements and muscle activation. To test our hypothesis, in Aim 1 we will map presynaptic partners of CSNs in the brain. We will further determine whether those connections are functional (Aim 2). Finally, we will determine how pre-CSNs control forelimb skilled movements and muscle activity (Aim 3). These results will provide the necessary framework for not only defining spinal motor circuitry, but also subsequent development of novel targeted interventions to treat motor disabilities.