Deconstructing antiseizure mechanisms of anterior thalamic nucleus electrical stimulation

PROJECT SUMMARY/ABSTRACT Epilepsy is one of the most prevalent neurological disorders. Patients with epilepsy experience abnormal brain activity causing seizures or periods of unusual behavior, sensations, and often loss of awareness or consciousness. Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is an approved therapy that effectively reduces seizures in many patients with drug resistant epilepsy, but very rarely leads to all-important complete freedom from disabling seizures. This gap in treatment effectiveness may stem from limited understanding of the mechanism underlying ANT-DBS, as it remains unknown not only which areas of a complex neuronal network ANT-DBS must modulate, but also how those structures are modulated, to achieve its therapeutic effect. We hypothesize that ANT-DBS results in direct, local inhibition of ANT neurons, and its downstream pathway. We propose a set of experiments to identify and modulate the neuronal network components that mediate ANT-DBS effectiveness, using the intrahippocampal kainic acid mouse model of temporal lobe epilepsy. We will first determine whether ANT neurons contribute to the seizure suppressive effect of ANT-DBS by ablating or modulating subpopulations of intrinsic neurons (Aim1). We then will examine whether the ANT-retrosplenial cortex (RSCx) pathway is a necessary conduit for ANT- DBS to be effective, by manipulating RSCx neurons that receive direct input from the ANT (Aim 2). Finally, we will test the hypothesis that ANT-DBS might suppress seizure by inhibiting afferent axons from areas projecting to the ANT, such as the mammillary bodies (Aim 3). Identifying the circuit mechanism of ANT-DBS would improve patient outcomes by leading to more precise guidelines for improved device targeting, prediction of patients that respond to ANT- DBS, and pave the way for novel therapies that can target this seizure-resistant network or use similar mechanisms.