The proposed study "Pathophysiology of dystonia" was designed with the goal of improving our understanding of dystonia and ultimately, developing improved therapies for this devastating condition. Dystonia is the third most common movement disorder and is characterized by ineffective, twisting movements and contorted postures. Experts in the field are increasingly recognizing that pathological alterations in discharge patterned activity are likely to be the key to understanding dystonia;yet, to date, this had not been systematically investigated previously in animal models of dystonia. Largely because little is known about the underlying pathophysiology of dystonia and because of a lack of adequate animal models, no therapies have even been introduced specifically to treat dystonia. Here we propose to conduct a systematic investigation of dystonia in the jaundiced Gunn rat model. Our group has worked extensively to advance the Gunn rat model to be able to induce reliable dystonia. Moreover, we have developed a number of methodological advances towards the proposed comprehensive investigation of the underlying pathophysiology of dystonia. Our preliminarily data demonstrate highly synchronized movement-related alterations in neuronal discharge activity in basal ganglia nuclei, including pauses in the globus pallidus (GP) and bursts in the entopeduncular nucleus (EP) in dystonic Gunn rats. In the ventrolateral (VL) thalamus, which receives the principal outputs from the basal ganglia, we discovered the discharge activity to be dominated by rhythmical burst activity. This unexpected pattern is normally thought to be reserved for higher order corticothalomocortical neurons and is distinct from the tonic mode normally used by thalamic relay neurons to transmit detail oriented signals to the cortex. From these preliminary findings, our overarching hypothesis is that dystonia is caused by exaggerated silencing of neuronal discharge activity in GP leading to excessive and abnormal basal ganglia outflow drive to the motor cortex via the thalamus.
Our specific aims (SAs) will test this hypothesis: SA 1., to determine the relationship between abnormally patterned multi-neuronal discharge activity in single basal ganglia and thalamic nuclei and the motor manifestations of dystonia, SA 2., to establish which discharge alterations in intrinsic basal ganglia nuclei are essential and to delineate the temporal relation of the pathological signaling between these basal ganglia nuclei, and SA 3., to define the physiological abnormalities along the pallidal- thalamic outflow pathway that ultimately contribute to abnormal cortical signaling in dystonia. In SA 1, we will record extracellular discharge activity from large numbers of neurons in single basal ganglia nuclei (GP, EP, and the subthalamic nucleus (STN)) and VL, while simultaneously examining electromyographic activity (EMG) from multiple muscles in normal and dystonic Gunn rats;in SA 2, we will simultaneously record in GP, STN and EP and collect EMG activity before and after placing fiber-sparing ibotenate lesions in GP and STN;and in SA 3, we will simultaneously record in EP, VL and primary motor cortex (MC) and collect EMG activity before and after placing lesions in EP and VL. We are confident that the findings from the proposed studies will broaden our understanding of the physiological bases for many forms of dystonia and, in so doing, reveal new targets for mechanistically-based approaches to treating dystonia. Further, our proposal is anticipated to contribute new basic knowledge of the role of the basal ganglia and thalamus and challenge current basal ganglia thalamocortical models.
The research proposal will investigate a devastating condition called dystonia. Dystonia prevents normal movements, which instead appear as twisting, distorted attempts to move, and in more advanced cases, causes the afflicted to be chair and even bed bound. Even though dystonia is considered the third most common movement disorder, no therapies have ever been designed specifically to treat this condition. While there are many causes, Veterans often commonly get dystonia as part of such other conditions as strokes and Parkinson's disease. Here we propose to study the brain signaling abnormalities in a rat model of dystonia with the ultimate goal of designing better therapies for dystonia. These results can be expected to have a great impact on the lives of Veterans.