Thursday, June 5, 2025
6/5/2025
Theta Phase-Locked Stimulation of Entorhinal-Hippocampal Inputs in Healthy and Epileptic Mice - Project Summary Epilepsy is a debilitating neurological disorder characterized not only by spontaneous recurrent seizures, but also severe cognitive deficits that present a significant detriment to quality of life. Changes in synchrony within and across brain regions have been implicated in temporal lobe epilepsy (TLE), but it is unclear how these changes contribute to memory deficits. Electrophysiological recordings from the Shuman lab have shown that coherence between the hippocampus and medial entorhinal cortex (MEC) is disrupted in a mouse model of TLE. This synchronization between hippocampus and MEC has been theorized to be important for spatial memory by allowing efficient information transfer at distinct phases of theta. However, there have been few causal studies on the impact of synchronization due in part to limited technical methods to manipulate the timing of inputs in behaving mice. Thus, investigating the causal nature of altered synchrony in cognitive dysfunction requires the application of novel tools to precisely manipulate the timing neural activity. To address this gap, I have developed a closed-loop optogenetic system that can stimulate neural populations at distinct phases of endogenous theta oscillations. In this proposal, I will use this system to test the hypothesis that the timing of MECII and MECIII inputs relative to endogenous theta oscillations controls memory performance in both healthy and epileptic mice. I will employ a head-fixed virtual reality task to test the effect of altered input timing on spatial memory performance and will investigate the role of this timing on other measures of synchrony including interregional coherence. I hypothesize that mistiming MEC inputs in healthy mice will impair memory performance and disrupt coherence, while restoring proper timing in epileptic mice will improve performance and increase coherence. Furthermore, I will use a layer specific viral approach to restrict optogenetic stimulation to afferents arriving to the hippocampus from MEC layer II or layer III and determine the distinct role of each of these inputs into hippocampus. Together, the results of these experiments will determine how the timing of inputs into the hippocampus impacts spatial processing in both health and disease and will pave the way for future therapeutic targets in epilepsy.
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