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.
