Learning-induced synaptic plasticity in corticospinal output neurons of motor cortex

PROJECT SUMMARY Learning is a fundamental process in the brain that enables flexible action—output can be adapted to develop novel behaviors or modify existing ones. This adaptation is necessary to survive in an ever-changing, dynamic environment. The process of learning is thought to be mediated by changes in circuit activity that are driven by experience-dependent modifications at relevant synaptic connections. However, the mechanisms by which learning-induced changes arise at the synaptic and circuit level remain unclear. In order to understand how neural activity is modified with experience in order to shape behavior, one must be able to measure each of these components over the process of learning. This type of measurement has yet to be performed due to technical limitations for measuring these features simultaneously. The research proposed here will use cutting- edge imaging methods combined with newly developed genetically-encoded sensors for monitoring neural activity to monitor changes in the brain during learning of a skilled motor task. Specifically, Aim 1 of this project will simultaneously measure synaptic and spiking activity in corticospinal projection neurons in primary motor cortex. These neurons project directly to spinal cord circuits that control muscle activation; thus, understanding the role of synaptic plasticity at this node in the movement pathway can directly link activity at multiple levels, ranging from synaptic activity to behavioral output. Aim 2 of this project will develop a new behavioral task to specifically test the hypothesis that the function of plasticity in corticospinal neurons is primarily to improve the precision of during dexterous movements. Population activity measured over many days of training on this task will be used to determine how different movement patterns are represented in these neurons over the course of learning. Altogether, these experiments will provide deeper mechanistic understanding of the processes involved in transforming neural activity during learning. Additionally, the insights from the proposed study have broader implications for understanding the brain during natural behavior, since motor learning is required to perform many ethological behaviors (e.g. hunting, foraging, escaping from predators), as well as disease, since deficits in motor learning present as primary or secondary symptoms in many neurological diseases. Lastly, the findings here will have high relevance to understanding capacity for plasticity in the corticospinal circuit to alter motor output, which can inspire new opportunities for the development of therapeutic treatments for patients with spinal cord injuries.