PROJECT SUMMARY This proposal targets temporal lobe epilepsy (TLE) a common form of acquired and drug resistant epilepsy often associated with a higher risk for cognitive deficits. It is becoming more vital to not only treat chronic seizures, but to also improve the quality of life of those with TLE. Researchers believe that physical activity and exercise functions to reduce seizure frequency and alleviate epileptic comorbidities such as memory loss. However, our understanding of how exercise contributes to these positive effects on epilepsy is limited. Alterations in epigenetic gene transcription programs in the central nervous system are associated with increased seizures, status epilepticus (SE), and the development of epilepsy. We have collected data suggesting that epigenetic mechanisms such as DNA methylation (DNAme) are significantly modified by chronic exercise in epilepsy. Therefore, we propose to test the overarching hypothesis that exercise triggers therapeutic DNAme changes in the epileptic hippocampus, contributing to the effects of exercise in epilepsy. We will use a multidisciplinary approach to test our hypothesis, including, state of the art in vivo CRISPR/dCas9 gene activation, next- generation sequencing, and memory/behavior tasks to: 1) Determine whether chronic exercise triggers DNAme mediated transcriptional programs in the epileptic hippocampus; and 2) Determine if DNAme is sufficient for the effects of chronic exercise on memory improvements with epilepsy. We anticipate that these experiments will provide important new insights into the role of DNAme in the epileptic hippocampus triggered by chronic exercise that will allow for the development of novel epigenetic therapeutic interventions for the mitigation of memory loss associated with epilepsy.