Project Summary Traumatic brain injury (TBI) affects 2.8 million people in the US annually, but despite the heightened awareness and community interest in TBI, there are no effective interventions for TBI associated morbidities, especially cognitive impairment. Interestingly, more than 50% of patients with TBI show cortical spreading depolarizations (SDs) during their hospitalization. These “brain tsunamis” are a predictor of mortality and morbidity after injury. Despite the fact that SDs occur often after TBI, the combined impact of SDs and TBI is unknown. The present study will determine the impact of SDs on TBI-induced pathology, providing critical guidance for targeted therapeutic intervention. Our overall hypothesis is that the occurrence of spreading depolarizations after TBI exacerbates brain pathology and is especially disruptive of hippocampal function. We will test this by inducing SDs in a rat model of TBI and addressing three specific aims. In Aim 1 we will investigate whether TBI+SDs causes greater injury pathology and aberrant neurogenesis. In Aim 2 we will determine whether SDs lead to deficits in hippocampal dependent behaviors and epilepsy. In our exploratory Aim 3 we will conduct single cell RNA sequencing on hippocampal dentate gyrus cells to identify cell-type specific molecular disturbances to guide future studies. The proposal will allow Dr. Ngwenya to learn new experimental and analytic techniques that will aid in her development as an independent researcher and position her to ask and answer the largest possible questions in translational neuroscience.