Corticospinal neurons in response control and movement coordination

为了在不断变化的环境中导航，我们必须不断地处理感官信息，以做出明智的决定，并执行目标导向的动作。这种在避免“不适当”或不想要的行动的同时产生“适当的目标”行动的过程被称为反应控制，它是我们生存所必需的日常生活的重要组成部分。想象一下战斗机飞行员在山区进行低空飞行演习。飞行员使用她所有可用的感官、视觉流动、声学指示器和本体感觉反馈来确保她产生有目的的自愿操纵杆运动，目标是选择适当的飞行路线。与此同时，镇压可能会产生重大和有害后果的不受欢迎的运动。反应控制和运动协调过程的中心是大脑中一个被称为运动皮质的区域，它包含数千个神经元(即在神经系统周围传递信息的电可兴奋细胞)，最终产生驱动我们肌肉和帮助我们移动的“命令”信号。在运动皮质中嵌入了一种特殊类型的输出神经元，称为皮质脊髓神经元(CSNS)，它将投射从大脑发送到脊髓，直接影响肌肉的激活。尽管对运动系统进行了数十年的深入研究，但我们仍然不能完全理解数千个CSN是如何在时间和空间上组织它们的活动，以在目标定向的运动中产生有效的反应控制和肢体协调。以前的工作表明，单个CSN的活动发生在动作选择发生的时间段，即所谓的动作准备阶段，以及整个动作执行阶段。大多数CSN显示与运动相关的活动增加，这与肌肉激活所需的下行运动命令的产生一致。然而，在同一时期，相当大比例的CSN表现出活动减少，这表明CSN输出的双向变化可能是有效选择和执行自愿运动的先决条件。这些早期的相关研究提供了CSN在运动控制中发挥重要作用的第一个证据，但我们缺乏对CSN活动如何跨运动皮质组织、这些神经元的输入如何随时间影响或塑造其活动以及阻止CSN输出如何影响反应控制和运动协调的更深入了解。为了解决这个问题，我们将训练小鼠执行一项听觉提示运动任务，目标是将操纵杆移动到向前或向后奖励区域(想想上面的战斗机飞行员类比)以获得液体奖励。这种以目标为导向的任务允许探索反应控制和运动协调。我们将结合使用不同的大脑记录技术和实时操纵神经元活动的方法来尝试和理解密集的CSN群体如何在任务执行期间组织他们的活动，以及这些活动模式对高效完成任务的重要性。我们的发现将对理解CSNS如何执行我们四肢的适当运动具有重要意义，这是完善当前运动控制理论的重要一步。

To navigate through our ever-changing environment, we must continually process sensory information to make informed decisions and execute goal-oriented movements. This process of generating 'goal appropriate' actions whilst avoiding 'inappropriate' or unwanted actions is known as response control and is an essential component of everyday life necessary for our survival. Think of a fighter pilot on a low flying exercise through a mountainous area. The pilot uses all her available senses, visual flow, acoustic indicators, and proprioceptive feedback to ensure that she generates purposive voluntary movements of the control stick with the goal of selecting the appropriate flight path out of the mountains. All the while suppressing unwanted movements that would have significant and unwanted consequences. Central to the process of response control and movement coordination is an area of the brain known as the motor cortex which contains thousands of neurons (i.e., electrically excitable cells that convey information around the nervous system) that ultimately generate the 'command' signals that drive our muscles and help us move. Embedded within motor cortex are a particular type of output neuron named corticospinal neurons (CSNs) which send projections from the brain to the spinal cord to directly influence muscle activation. Despite decades of intensive investigation of the motor system, we still do not fully understand how thousands of CSNs organise their activity in time and space to generate efficient response control and coordination of our limbs during goal-directed movements. Previous work has shown that changes in the activity of single CSNs occur during the period when movement selection occurs, the so-called movement preparation phase, and throughout movement execution. Most CSNs show movement-related increased activity consistent with the generation of descending motor commands necessary for muscle activation. However, a significant proportion of CSNs display reduced activity during the same period, suggesting bidirectional changes in CSN output may be a prerequisite for efficient selection and execution of voluntary movements. These early correlative studies provided the first evidence that CSNs play an important role in motor control, but we lack a deeper understanding of how CSN activity is organised across motor cortex, how inputs to these neurons influence or shape their activity over time and how blocking of CSN output affects response control and movement coordination.To address this, we will train mice to perform an auditory cued motor task where the goal is to move a joystick to either a forward or backward reward zone (think of the fighter pilot analogy above) to receive a fluid reward. This goal-oriented task allows the exploration of both response control and movement coordination. We will use a combination of different brain recording techniques combined with approaches to manipulate the activity of neurons in real-time to try and understanding how dense populations of CSNs organise their activities during task execution and the importance of these patterns of activity for efficient task completion. Our findings will have important implications for understanding how CSNs execute appropriate movement of our limbs constituting an important step towards refining current theories of motor control.