Our proposal seeks to unite two powerful tools in contemporary neuroscience: brain recordings from awake, behaving individuals and large-scale gene expression from human brain tissue. We hope to understand more about cognitive function in epilepsy and other disorders by studying gene expression profiles linked with brain oscillation information. The key innovation of this proposal is the collection of these two types of data from the same patients at different stages of their evaluation and treatment for epilepsy. In our first aim, we will build upon our recent findings examining gene/oscillation correlations through the generation of a proposed new large dataset of brain oscillations and by extending our analysis to include item retrieval during episodic memory. In our second aim, we will build an entirely new dataset by collecting intracranial EEG oscillatory data as subjects perform an episodic memory task and then also collect temporal lobe tissue specimens from the same patients. This is because the patients first undergo seizure mapping with intracranial electrodes, and then undergo resection of the temporal lobe. This offers the possibility of capturing oscillatory and gene expression data from the same tissue across subjects. In our third aim, we will generate gene expression data from surgical epilepsy patients and compare these profiles to datasets derived from cadaveric tissue samples. These comparisons will serve as a control to help interpret our correlation results and as a substantial contribution to the literature in its own right. Although this ambitious plan requires close integration between labs with expertise in gene expression analysis and signal processing, and requires a pipeline for processing tissue obtained in the operating room as well as specific surgical techniques to produce good specimens, the methodological groundwork we have established and preliminary data we show demonstrate that our plans have a high chance of success. The genes we identify as being highly correlated with mnemonic processing will be strong candidates for further animal experimentation and potential therapeutic targeting. We believe this line of investigation is a novel way to address the problem of cognitive decline in epilepsy and potentially other disorders such as mild cognitive impairment.
Knowledge of the molecular mechanisms underlying human memory should provide therapeutic insights into cognitive disorders that involve memory loss such as epilepsy. The proposed studies will build upon our recent work that has laid the groundwork for identifying the genes associated with memory performance in humans, by creating an entirely new dataset in which the same set of epilepsy surgical patients provides both brain oscillation and gene expression data. Our results should provide new genes to stimulate mechanistic studies in animal models as well as molecular pathways for therapeutic targeting in patients with epilepsy who suffer cognitive decline.
