The knob supination task: a sensitive test of corticospinal function in the rat

 描述(申请人提供)：皮质脊髓束(CST)将启动运动的运动皮质直接连接到执行运动的脊髓回路。我们的实验室研究CST是因为它是自主运动的主要途径，而且CST损伤在很大程度上是脑或脊髓损伤后失去运动的原因。神经损伤和修复领域主要研究大鼠，但缺乏对其CST功能的良好行为测量。目前对大鼠前肢运动的测试采用：1)对CST损伤不敏感的一般功能，2)不测量本身损害的爪子偏好，或3)特定运动的定性测量。我们发现，与人类一样，大鼠失去了翻转爪子的能力--从手掌向下转到手掌向上--伴随着CST损伤。旋后功能的丧失严重限制了手的功能，这主要是因为阻止了手的正确位置来进行操作。我们假设，量化大鼠的前肢旋后活动将是一项敏感的CST功能测试。我们创造了一个运动任务，迫使老鼠后仰，以获得食物奖励。从伸手的盒子里，老鼠在后仰时抓住并转动一个旋钮。安装在旋钮上的旋转编码器测量角度位置。计算机不断记录旋钮的角度，如果它将旋钮旋转到超过标准角度，就会给老鼠一个小球奖励。这使得我们第一次能够以一种高度定量的方式测量旋后作用。此外，测量是自动化的，使数据收集比需要手动评分的测试容易得多。在目标1中，我们将测量旋钮旋后任务对CST功能障碍的敏感性。我们将测量使用GABA激动剂Muscimol药物灭活运动皮质前后的前肢功能。我们将测试一系列稀释的蝇草酚--从产生完全失去旋后功能的高浓度到产生轻微损伤的低剂量。我们将比较失活对旋后任务的影响与单一颗粒到达任务的表现，这是一项金标准测试。基于我们的初步结果，我们假设旋后任务将比标准的前肢功能评估更敏感。在目标2中，我们将量化锥体切开术(一种广为接受的CST损伤模型)前后的前肢功能，再次通过比较旋后作业和小球到达。我们假设，锥体切开术将在旋后任务中产生更大的损害，大鼠将在损伤后的几周内部分恢复技能，与我们的初步结果类似。这种模式 对于有CST损害的人来说，丢失和部分恢复是典型的，例如中风。拥有一个模拟人类功能的大鼠模型对于了解CST功能是如何通过损伤诱导的可塑性改善的将是重要的。CST功能的灵敏分析也将是至关重要的 用于测量电机系统的维修，这是我们实验室的目标。对人类来说，旋后的灵敏方法已经存在；在大鼠身上进行类似的测量，可以帮助将大鼠身上有希望的治疗方法转化为临床试验。

 DESCRIPTION (provided by applicant): The corticospinal tract (CST) connects motor cortex, which initiates movement, directly to the spinal circuits that execute movement. Our lab studies the CST because it is the principal pathway for voluntary movement and because CST injury is largely responsible for loss of movement after brain or spinal cord injury. The neural injury and repair field primarily studies rats, but we lack good behavior measures of their CST function. Current tests of forelimb movement in the rat employ: 1) general functions that are insensitive to CST injury, 2) paw preference without measuring impairment per se, or 3) qualitative measures of specific movements. We have found that rats, like humans, lose the ability to supinate the paw-turn it from palm down to palm up-with CST injury. Loss of supination severely limits hand function, mostly by preventing the hand from being properly positioned for manipulation. We hypothesize that quantifying forelimb supination in the rat will be a sensitive assay of CST function. We have created a motor task that forces rats to supinate in order to receive a food reward. From a reaching box, rats grasp and turn a knob in supination. A rotary encoder attached to the knob measures angular position. A computer continuously records knob angle and rewards the rat with a pellet if it turns the knob beyond a criterion angle. This allows us, fo the first time, to measure supination in a highly quantitative way. In addition, the measurement is automated, making data collection much easier than tests that require manual scoring. In Aim 1, we will measure the sensitivity of the knob supination task for CST dysfunction. We will measure forelimb function before and after pharmacological inactivation of motor cortex with the GABA agonist muscimol. We will test serial dilutions of muscimol-from a high concentration that produces complete loss of supination to a low dose that produces minor impairment. We will compare the effects of inactivation on the supination task with performance of the single pellet reaching task, a gold standard test. Based on our preliminary results, we hypothesize that the supination task will be more sensitive than the standard assessment of forelimb function. In Aim 2, we will quantify forelimb function before and after pyramidotomy, a well-accepted CST lesion model, again by comparing the supination task with pellet reaching. We hypothesize that pyramidotomy will produce greater impairment in the supination task and that rats will partially regain the skill in the weeks following injury, similar to our preliminary results. This pattern of loss and partial recovery is typical for people with CST lesions, such as stroke. Having a rat model that mimics human function will be important for understanding how CST function improves through injury-induced plasticity. A sensitive assay of CST function will also be critical for measuring motor system repair, which is the goal of our laboratory. Sensitive measures of supination already exist for people; having homologous measures in rats could help translate promising therapies in rats to clinical trials.