NSF Award
1734813
How activity of individual brain neurons results in the emergence, spread, and eventual termination of seizures is a basic and unsolved issue. Extensive research has examined brain activity during seizures using invasive and non-invasive tools, but there is a gap in our understanding of the cellular-level basis of large-scale phenomena such as seizures. Here, Dr. Sarah F. Muldoon (University at Buffalo, SUNY) and Dr. Ethan M. Goldberg (The Children's Hospital of Philadelphia and The University of Pennsylvania) use methods for recording neural activity from multiple single neurons in mice, as well as methods for recording large-scale neuroelectric activity (EEG), to identify groups of neurons whose activity is associated with time-evolving features of seizures. This project combines newly developed theoretical and computational neuroscience approaches with state-of-the art experimental techniques for imaging and manipulating brain activity. It evaluates a novel hypothesis that transitions to seizure onset and between seizure sub-states represent changes in the activity of small, identifiable clusters of neurons, and that such clusters can be identified and manipulated to modulate seizures. This multidisciplinary collaborative approach is expected to produce novel insights into the mechanisms of seizure generation and propagation, inform novel treatments for epilepsy, and provide a framework generalizable to larger efforts to link data related to changes in brain state across scales.<br/><br/>Recent work suggests a fine-grained and evolving heterogeneity in individual neuronal dynamics during seizures. However, relatively little is known about the relationship between single neuron activity and large-scale seizure dynamics. Here, we combine multilayer network theory with two-photon calcium imaging in an experimental in vivo epilepsy model to identify functional cell assemblies (small groups of neurons with similar, functionally-relevant activity patterns) associated with transition to and between seizure states. We characterize the ability of defined subsets GABAergic inhibitory interneurons to impact cell assembly dynamics, using optogenetics to manipulate interneurons to interrupt transition to seizure. The overall goal of this proposal is to develop a means for rapid detection of spatially- and functionally-defined neuronal assemblies associated with these sub-state transitions so as to predict and manipulate such transitions. The results will provide the first large-scale imaging data on the cellular architecture of epileptic seizures in vivo as well as a set of novel tools for the analysis of such data. This work will lead to the development of neural control strategies designed to specifically target subpopulations of neurons that have been functionally identified as key elements in driving epileptic dynamics.<br/><br/>This project is funded by Integrative Strategies for Understanding Neural and Cognitive Systems (NSF-NCS), a multidisciplinary program jointly supported by the Directorates for Computer and Information Science and Engineering (CISE), Education and Human Resources (EHR), Engineering (ENG), and Social, Behavioral, and Economic Sciences (SBE).
