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

 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.

 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.