The ability to link elementary actions together to perform a meaningful sequence of movements is a key component of voluntary motor behavior. Many of our daily motor tasks (e.g., handwriting, typing, etc.) depend on attaining a high level of skill in the performance of sequential movements. Consequently, the neural basis of skill acquisition and retention is a fundamental problem of systems neuroscience. To explore the cortical involvement in this behavior we will use optical imaging and single neuron recording to define patterns of activity in the primary motor cortex (Ml) and the dorsal premotor area (PMd) as monkeys learn to perform and practice sequences of movements. We will monitor activity at various times in relation to an animal's level of skill acquisition and task performance. The data from optical imaging and single neuron recording are likely to provide fundamental insights into the neural basis of motor skills. However, both techniques are correlational approaches. To test causality, we will make micro-injections of various pharmacolgic agents in M1 and the PMd to disrupt local neuron activity, protein synthesis and ERK signaling. We will determine the effects of these micro-injections on the acquisition, performance and retention of motor skills. Taken together, the proposed studies will provide some novel information on the cortical mechanisms that underlie a critical aspect of human behavior- the acquisition and retention of motor skills. In addition, there is growing evidence that many of the mechanisms of plasticity that are used to acquire new skills may also be available to promote recovery of function following traumatic brain injury or stroke. Thus, the new insights gained from the proposed experiments may suggest novel rehabilitation strategies for restoring motor function. RELEVANCE (See instructions): The proposed work is central to the problem of understanding the mechansims where practice leads to to reorganization of the human motor system in the face of aging, neurodeneration, stroke or brain injury. Understanding these mechansims has an impact on the design of therapies directed at preserving function, developing compensator movements and ultimately, developing novel motor capacity.