Multiple Sclerosis (MS) is a disease where the immune system attacks the brain and spinal cord. The resulting disability can range from vision loss in one eye or complete paralysis. After years of suffering from this disease, most people enter a phase called progressive MS where available treatments are no longer able to prevent the increase in disability of most people. Progressive MS is so hard to treat because its cause(s) is unknown. However, others and I think the underlying causes of progressive MS might be different from those in the early stages of the disease. Therefore, to study progressive MS, we will use an animal model of progressive MS and examine the role of the brain’s immune cells, called microglia. We know from brain imaging studies in people with progressive MS that microglia play a role in this stage of the disease because we see microglia activity associated with more physical disability. Historically, study microglia was challenging because they could not be differentiated from cells known as blood-derived macrophages. For example, microglia contain similar proteins (referred to as “markers”) to as blood-derived macrophages. The similarity in markers prevented scientists from understanding which functions or toxic properties can be attributed to which cell. To examine the specific role of microglia in a progressive MS animal model, I have developed new tools to distinguish between microglia and blood-derived macrophages. I will use these new tools to track microglia during the disease course of our progressive MS animal model and study the activity and function of these cells. I will also remove microglia in our animal model, to understand if microglia initiate or propagate damage. In the end, we hope to understand the role of microglia in this animal model, so that we can find new MS therapies that target microglia directly.