Plasticity of cortical motor networks is a critical mediator of skilled motor learning and a potential mechanism for supporting the rehabilitation of motor function after neurological injury. Fundamental to the understanding of how the remodeling of these cortical networks supports skilled motor control is the ability to record from identified cell types during the stages of skill acquisition and rehabilitation. Recent advances in two-photon imaging and the development of genetically encoded calcium indicators has allowed for an understanding of the dynamics of neural networks during motor learning. However, execution of the simple motor tasks currently in use in head- fixed mice are not sensitive to disruption of cortical motor networks, while more complex tasks currently require high speed video analysis and post-experimental processing. There is a critical need to develop unbiased testing devices for skilled, corticospinal-dependent behaviors to use in concert with modern in vivo imaging techniques. The long-term goal is to develop novel therapeutic interventions for the recovery of function after spinal cord injury through an understanding of the cellular and subcellular mechanisms that drive neural circuit remodeling. The overall objective for this proposal is to develop a system for assessing a complex, corticospinal-dependent behavior for use in future in vivo imaging studies of skilled motor learning and rehabilitation. In order to achieve this objective, the automated, objective supination task will be adapted for use in head-fixed mice during two- photon imaging. The rationale for developing this tool for use during in vivo imaging in head-fixed mice is that it will allow for the study of cortical motor networks during both the learning and rehabilitation of skilled, corticospinal-dependent, stereotyped forelimb movements in an unbiased manner in real time. The objective for this proposal will be met by addressing the following two specific aims: 1) Adapt a supination task for mice and determine the effects of corticospinal tract injury; and 2) Adapt the supination task for use in head-fixed mice and validate its use for the study of corticospinal neuron activity in vivo. Under the first aim, a reduced scale version of the Vulintus, Inc. MotoTrak rat supination task will be adapted for mice in concert with Vulintus, Inc., after which the effects of corticospinal tract injury will be tested on the supination task. Under the second aim, the supination task will be adapted for head-fixed mice and calcium transients will be used to study the response of corticospinal neurons to injury. The proposed work is innovative in that it will result in novel tools for the study of skilled, corticospinal-dependent motor learning and the activity of cortical motor networks in vivo in a quantitative, reproducible, and unbiased manner. The proposed work is significant as it will allow for vertical advancements in the study of skilled motor learning and rehabilitation after neurological injury. Ultimately, these tools have the potential to be applied broadly to study both the mechanisms of motor learning and the effects of neurological dysfunction, whether developmental or induced by injury and disease.
The proposed research is relevant to public health as the techniques developed will be broadly applicable to evaluating potential therapeutic strategies for spinal cord injury, stroke, traumatic brain injury, as well as developmental and neurodegenerative diseases. The proposed work is relevant to the NIH?s mission as it could have far reaching applications in the study of motor learning as well as an understanding of learning- related mechanisms during rehabilitation.
