ALS is a disease that is characterized by degeneration of both upper and lower motor neurons, and while a significant proportion of work has focused on motor neurons in the spinal cord, the motor cortex in the brain, where electrical signals to your muscles originate have clear, but poorly understood involvement in the disease process. One of the hypotheses in ALS is that excessive activity of upper motor neurons may be an early sign of the disease and Dr. Lisa Topolnik, an expert in brain circuitry (understanding how the various brain neurons interact), has developed a unique system to study whether this is a result of abnormal actions of other neurons (called interneurons) in the motor cortex that should be moderating this neuron firing. In this Discovery Grant, Dr. Topolnik will use brain imaging to examine the effects in motor cortex when ALS model mice are using their muscles prior to and at onset of disease symptoms. If the hypothesis that these interneurons are failing to inhibit excessive upper motor neuron activity is true, Dr. Topolnik will examine the effect of various treatments to circumvent this effect. Ultimately this is an example of how expertise outside the field of ALS can be made applicable to answer key questions that have not been previously examined and this work will undoubtedly yield new insight into how the disease is caused, with further potential to discover novel treatments as well.