The broad, long-term goals of the proposed research are to better understand the neural underpinnings of healthy motor function and motor dysfunction in Rett syndrome. Rett syndrome is a neurological disorder, typically resulting in severe cognitive and motor disability. Rett syndrome is associated with an imbalance between excitatory and inhibitory neurons in many brain regions, including motor cortex. One specific aim of the proposed research is to determine how population coding of body movements is altered by pharmacologically-imposed imbalance between large populations of excitatory and inhibitory neurons in healthy motor cortex of rats. A second specific aim of the proposed work is to identify what goes wrong in the motor cortex of a transgenic rat model of Rett syndrome. The research will test the hypothesis that imbalanced excitation and inhibition results in a corruption of the motor output signals from cortical neurons. This corruption is hypothesized to occur due to a breakdown of the distinction between “internal” and “external” neurons in motor cortex. In healthy motor cortex, internal neurons are rather noisy and unrelated to motor output, while external neurons are less noisy and responsible for motor output. Confirmation of this hypothesis in motor cortex of rat models of Rett syndrome has the potential to reveal new strategies for ameliorating the motor difficulties faced by those with Rett syndrome. More specifically, pharmacological restoration of a more balanced interaction between excitatory and inhibitory neurons could improve the signal quality of motor output neurons, thus improving motor function. To test this hypothesis, the proposed research would use multi-electrode brain implants to monitor the activity of many single neurons in motor cortex of rats as the animal moves freely and performs motor tasks. Simultaneously with the neural recordings, the body motion would be tracked in three dimensions with high precision. Innovative data analysis will be brought to bear on these body and brain measurements, comparing transgenic and wild type rats. This research has the potential to substantially advance understanding of population motor coding and motor dysfunction in Rett syndrome.