Optogenetic and chemogenetic manipulations of striatal output pathways for seizure control

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Project Abstract Deep brain stimulation for epilepsy is growing in use, and offers promise to patients for whom other treatments fail. Thus, identifying new targets for stimulation is of considerable clinical and translational interest. The basal ganglia (BG), which have been explored extensively for stimulation in movement disorders, also may be attractive targets for epilepsy. Preclincial studies show that modulating activity in BG nuclei such as the striatum and substantia nigra pars reticulata (SNpr) can potently suppress experimental seizures in acute models of epilepsy. However, the network mechanisms underlying this effect, and the degree to which this translates into models of chronic epilepsy remain unknown. This NRSA F30 proposal requests four years of support. During years 1 and 2, I plan to complete my doctoral thesis. The thesis will encompass the two aims presented in the following research plan that have been heavily updated to reflect my research progress since the submission of the original proposal. In aim 1, I will test the hypothesis that on-demand optogenetic silencing of the SNpr will suppress spontaneous seizures in chronically epileptic rats. In parallel, I will test the hypothesis that on-demand activation of the striatum will produce an equivalent suppression of spontaneous seizures. While these manipulations are well-studied in acute seizure models, these studies would be the first to evaluate the anticonvulsant potential of these regions in chronic epilepsy. During the course of this aim, I will learn the status epilepticus model of chronic epilepsy in rats and the set up of self-contained, automated systems to monitor their seizure activity. In aim 2, I will use fiber photometry to test the hypothesis that seizure activity progressively and differentially engages basal ganglia output pathways. I will also test the hypothesis that optogenetic manipulations that counteract pathological recruitment of striatal pathways will suppress seizures. The training in this aim includes learning the technical aspects of fiber photometry as well as coding and data analysis methods. Throughout the course of my doctoral research, I will continue to be trained in physiological and histological methods as well as general skills and career development. After I complete my thesis defense, I will complete my pre-doctoral medical training during years 3 and 4 of the fellowship period. Clinical training follows a standardized institutional curriculum. After this period of joint-degree training, I plan to apply to combined residency/fellowship tracks in physician-scientist training programs in neurology/epileptology. In sum, during the proposed fellowship period, I will gain expertise in cutting-edge techniques in neurophysiology concurrent with training in intellectual and practical career development. The work proposed will benefit the field by determining mechanisms of seizure propagation and restraint via basal ganglia nodes while also testing them as candidates for the management of chronic spontaneous epilepsies.