Progression of Entorhinal-hippocampal Spatial and Emotional Processing Deficits in a Mouse Model of Temporal Lobe Epilepsy

点击翻译按钮获取中文摘要

PROJECT SUMMARY Temporal lobe epilepsy (TLE) is a debilitating disorder characterized by spontaneous and recurring seizures as well as pervasive memory and psychiatric impairments. These TLE-induced comorbidities do not respond to pharmacological treatment, and little is known about how specific brain circuits are altered by disease to drive these clinical phenotypes. Recent evidence suggests that these comorbidities are driven by deficits along the dorsoventral axis of the entorhinal-hippocampal circuit and that they are dissociable from seizures themselves. As such, it is imperative to study how epilepsy may detrimentally alter temporal lobe circuitry that is a key node in memory and emotion processing. In previous work, our lab and others have established CA1 of dorsal hippocampus (dCA1) as a site of poor spatial processing in epileptic mice. However, it remains unclear if upstream inputs to dCA1 are impaired which may be driving downstream changes in hippocampus. In the F99 phase, I will test the hypothesis that medial entorhinal cortex (MEC) has disrupted spatial coding in epileptic mice and will specifically test how distinct hippocampal inputs from layer 3 (MECIII) pyramidal neurons and layer 2 (MECII) stellate cells are altered. I will perform in vivo calcium imaging in these isolated subpopulations as epileptic and control mice perform spatial foraging and memory tasks, both before and after the onset of progressive memory impairments. This will allow me to determine the relationship between these spatial coding metrics and progressive memory deficits found in epileptic mice. During this phase I will receive technical training on in vivo calcium imaging and large-scale data analysis, as well as conceptual training on epilepsy models, learning and memory circuits, spatial coding, and integrating neural recordings with behavior. In the K00 phase, I plan to combine my previous expertise in stress-induced changes in entorhinal- hippocampal signaling with my current work in epilepsy circuits to determine how the ventral extent of this circuit contributes to altered emotional regulation in epilepsy. I will combine state-of-the-art mouse behavior, molecular assays, gene expression studies, calcium imaging, and virally mediated manipulation techniques to characterize ventral entorhinal-hippocampal circuit changes that drive psychiatric symptoms in epilepsy. Results from these studies will provide new insights into the neural and circuit mechanisms of epilepsy induced emotion deficits. Together, this training across F99 and K00 phases will support my successful transition to postdoctoral researcher and ultimately a career as an independent research scientist focusing on molecular, cellular, behavioral, and circuit-level signatures of behavioral dysfunction associated with epilepsy and stress.