Dystonia is a devastating condition characterized by ineffective, twisting movements and contorted postures. While surgical treatments are effective for those with many genetic or undetermined causes, treatments for secondary forms due to such as trauma, strokes and cerebral palsy are poorly responsive to current medical and surgical therapies. Because of the high incidence of dystonia from head trauma, our soldiers are particularly susceptible to developing secondary dystonia. Despite its impact on human health, the underlying abnormalities in the brain had not prior to our recent studies been well investigated in animal models. Our investigations in rodent models of dystonia are revealing remarkable insight into how abnormal signals originating in the basal ganglia, located in a deep region of the brain, are causing another deep brain region, the thalamus, to send abnormal signals onto the motor cortex at the surface of the brain. The abnormal brains signals thus generated in the motor cortex ultimately lead to erroneous signals being sent to the muscles, causing the devastating motor features of this condition. We discovered that the neuronal (brain cell) activity in a specific part of the basal ganglia, the globus pallidus externa (GPe) was grossly silent in rodents with experiment dystonia from being jaundiced in their brain. This led us to pursue destructive chemical lesions in GPe in other rodents to further test if silencing the GPe would indeed produce dystonia. After affirming this, we developed a second much improved focused rodent model which will be invaluable for our ongoing studies. In the new studies, we will utilize a modern technique, which takes advantage of the properties of opsins, which are light-sensitive proteins contained in microorganisms, including bacteria. Opsins, like the light receptors in the human eye, are important for producing actions in these microorganisms, such as movement, in response to light. By incorporating viral-opsin constructs directly into select brain cells and then passing a light probe through the brain near these cells, different colored light frequencies can be used to stimulate or inhibit the ?infected? brain cells with very high precision. These opsins will be used here to program the abnormal brain cell activity in previously defined pathological brain regions, including in different nuclei (regions) of the basal ganglia and the thalamus. Our intent is to program the brain cells in these regions to approach more natural patterned activity, with the hope of reversing the dystonia in the rodents. Additional methods will involve introducing a pharmacological agent into the thalamus to turn off electrical burst properties of these brain cells to determine the role of bursting of these brain cells in programming of normal and pathological movement. Brain cells in the thalamus exist in two states: a tonic firing mode and a burst firing mode and the importance of each has been debated. Our studies are showing that the burst mode is the main mode in the thalamus for motor actions and that the specific fine details of the bursts precisely influence movement activity. Since the details of the burst signaling are highly abnormal in dystonia, we will attempt to normalize this activity by stimulating opsins injected directly into the thalamus, as well as introduced into regions connecting to and influencing the thalamus. We will additionally extensively incorporate computational neuronal simulations to further test our physiological modeling and to guide our neurophysiological studies. Our comprehensive approach is anticipated to lead to refinement of our novel evolving normal and pathological basal ganglia- thalamocortical circuitry model. Ultimately, the hope is that the findings here will translate to new treatments for a condition which is often refractory to current therapies.
The research proposal will investigate a devastating condition called dystonia. Dystonia prevents normal movement, causing instead twisted, distorted attempts to move. In advanced cases, the afflicted is chair and even, bed bound. Even though dystonia is one of the most common movement disorders, no therapies have been designed specifically to treat this condition. Veterans are particularly at risk due to the frequent occurrence after head trauma and as potentially irreversible side effects of medications used to treat PTSD. In our last proposal we uncovered the underlying brain changes in key areas of the brain in dystonia. Here we propose to translate these findings by testing novel therapeutic approaches to reversing the dystonia in a rat model of dystonia. These results can be expected to have a great impact on the lives of Veterans.
