Long-term memory impairment significantly impacts patients with temporal lobe epilepsy (TLE), but no targeted treatment exists. There is a critical need to understand the mechanisms that disrupt long-term information stor- age in the epileptic brain. The long-term goal is to develop strategies to ameliorate and prevent cognitive impair- ment in patients with epilepsy. The overall objectives are to i) elucidate how interictal epileptic discharges (IEDs) affect hippocampal-cortical communication during memory consolidation, and ii) determine how closed-loop modulation of this communication alters long-term memory in an animal model of TLE. The central hypothesis is that IEDs disrupt the interaction of hippocampal ripples and cortical sleep spindles, altering neural activity patterns and plasticity. Further, restoration of physiologic hippocampal-cortical coupling can normalize the long- term memory deficits observed in TLE. The rationale for this project is that elucidating the spatiotemporally spe- cific network mechanisms that underlie long-term memory disruption will enable prevention of pathologic com- munication without impairment of physiologic communication, thereby facilitating memory consolidation. The central hypothesis will be tested by pursuing three specific aims in a TLE animal model: i) evaluate the effect of modulating hippocampal-cortical oscillatory coupling on neural spiking patterns; ii) determine the effect of mod- ulating hippocampal-cortical coupling on long-term memory, iii) establish links between large-scale molecular markers of synaptic plasticity and hippocampal-cortical oscillatory coupling during impaired memory consolida- tion. To accomplish these aims, in vivo electrophysiology and assays of immediate early gene expression will be paired with closed-loop electrical stimulation in freely behaving rats performing long-term memory tasks. The research proposed is innovative, in the applicant?s opinion, because it focuses on modulating neuronal commu- nication between brain regions during the interictal period to enhance memory consolidation. These contributions will be significant because they are expected to provide the mechanistic groundwork for development of novel approaches to treat, and potentially prevent, memory impairment in patients with epilepsy.
The proposed research is relevant to public health because it focuses on understanding neural network mecha- nisms underlying long-term memory impairment in epilepsy and testing closed-loop strategies for ameliorating this impairment. Such strategies offer the potential for a significant advance in addressing cognitive comorbidity in patients with epilepsy, in line with the NINDS mission to use mechanistic knowledge to reduce burden of neurological disease.
