Much of our behavioral repertoire consists of learned motor skills, yet little is known about the neural mechanisms underlying their acquisition and production. In mammals, motor cortex is thought to be integral for exploring and learning new motor outputs, but its specific role in complex motor sequence learning remains to be understood. Cortical injury and strokes in humans are often detrimental and lead to lifelong motor disabilities, but some learned motor skills can recover remarkably well from even very severe motor cortex lesions. Similarly, in rodent and non-human primate studies, lesions of motor cortex have been found to affect some behaviors more than others. The aim of this project is to explore whether the involvement of motor cortex in the acquisition and production of complex motor sequences depends on how the behavior is learned. Specifically, I will consider two common, but fundamentally different, strategies for acquiring motor sequences: (i) trial-and-error learning, in which the animal relies on exploratory actions and their outcomes for shaping the behavior, and (ii) instructive learning, in which sensory cues inform the behavior. I will develop a novel behavioral paradigm allowing rats to be trained on the same motor tasks, a temporally precise sequence of lever taps, using these different strategies. Rats learning through trial-and-error are rewarded for successive approximations to the final behavior, and rely only on their exploratory actions for converging onto the correct sequence. Rats learning the task by instruction have access to an external cue that indicates when to tap. In preliminary experiments we have successfully trained rats using both training paradigms. In both cases, animals developed highly precise and stereotyped motor behaviors that, once learned, were spontaneously expressed and stable. To investigate the extent to which motor cortex involvement depends on how a behavior is acquired, both training groups will be subjected to temporary inactivations or permanent lesions of specific regions motor cortex during different phases of learning. Performance before and after lesions will be carefully monitored using continuous and precise measures of behavior, derived from high speed movies. Initial studies, in which large parts of motor cortex was lesioned, produced very surprising results. Rats that learned the task through trial-and-error were unaffected by even very large lesions, while animals that had access to instructive cues during learning, showed no memory of the learned behavior following the lesions. These preliminary results suggest that the role and function of motor cortex in generating complex behaviors depend strongly on learning process. Understanding this learning-related distinction in motor cortex function, the main aim of my proposal, will speak to the etiology of motor disorders and disabilities and inform treatment and rehabilitation of patients with motor cortex injuries. PUBLIC HEALTH RELEVANCE: Cortical injury and strokes in humans are often detrimental and lead to lifelong motor disabilities, but some learned motor skills can recover remarkably well from even very severe motor cortex lesions. Which motor skills survive a cortical injury and why is a matter of debate. The aim of this project is to explore whether the involvement of motor cortex in the acquisition and production of complex motor sequences depends on how the behavior is learned.