Motor Sequence Learning in Basal Ganglia

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The fluid, seemingly effortless execution of sequences of movements is a ubiquitous feature of everyday motor skills. Ample evidence for their importance comes from the common human neuropathologies (Parkinson's disease, in particular) in which sequential skills are especially impaired. Long-term motor sequencing skills are formed, most likely, across multiple time scales in associative, premotor, and motor circuits of the brain. Recent evidence suggests that for each of these brain circuits, a sub-cortical loop through the basal ganglia (BG) contributes selectively to reinforcement-driven modulation of thalamo-cortical plasticity. These findings lead to the hypothesis that BG loops play central roles in the acquisition of sequence information, but are less important in the recall or use of already-learned sequences. The specific aims (SAs) of this proposal will test that general hypothesis by using non-human primates: 1) to determine if neurons in the globus pallidus interna (GPi, the primary BG output nucleus for skeletomotor function) preferentially encode sequence information during new learning; and 2) to test whether intact BG circuits are necessary for new sequence learning. Associative loops through the BG may play a greater role in the fast acquisition of flexible goal-directed representations of sequence information while the premotor and motor loops may mediate slow acquisition of habit-like effector-specific representations. We will infer the circuit membership of individual GPi neurons by stimulating different cortical areas and observing the orthodromic inhibitory effects. Animals will perform a discrete sequence production task using novel, familiar and over-trained sequences. SAl will test if neuronal encoding of sequence-specific information in associative, premotor, and motor circuits of GPi reflects the predicted roles of these circuits in learning novel, familiar, and over-trained sequences. SA2 will determine if an interruption of BG output (i.e., GPi inactivation or lesion) selectively impairs training-related improvements in sequence performance. The prediction is that inactivations or lesions in the associative BG circuit will impair novel sequence learning whereas lesions in premotor and motor circuits will block the further refinement and solidification of performance of already-familiar sequences. Results from these experiments will aid in understanding the physiological basis for RELEVANCE (See instructions): TThe 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.