Multipopulation voltage imaging for network insights in temporal lobe epilepsy

点击翻译按钮获取中文摘要

PROJECT ABSTRACT The hippocampus is a critical structure in mesial temporal lobe epilepsy (TLE), and is comprised of different cell types and subcircuits. How these circuit elements behave and importantly how they interact may provide key insights into epilepsy, including ictogenesis. Epilepsy is recognized as a “network disorder”; a proper understanding of network interactions in epilepsy is crucial to a full understanding of the disorder and consequently the development of novel treatment options. A new suite of voltage indicators allows unparalleled and simultaneous investigation of such circuit elements. We will therefore apply these cutting-edge methods in vivo, in awake, chronically epileptic animals, allowing us to answer questions not currently addressable with other methods – examining features including subthreshold membrane potential changes and resolving individual spikes even during high levels of activity. Using a mouse model of chronic TLE, we will image during periods free of overt epileptiform activity, during interictal spikes, during preictal periods, and throughout ictal activity, as well as postictal periods – providing us will a full picture of activity patterns across different ictal states. In this initial work, we focus on CA1 pyramidal neurons that project to the medial prefrontal cortex (PCmPFC) and CA1 pyramidal neurons that project to the medial entorhinal cortex (PCMEC), in addition to inhibitory neurons, including PV neurons specifically. These circuit elements were chosen due to their known and distinct interactions. Specifically, PCmPFC provide strong excitation to local PV neurons, but receive little inhibition from PV neurons. Conversely, PCMEC receive strong inhibition from local PV neurons but provide relatively limited excitation to PV neurons. We will therefore be able to examine, for the first time, how these circuit elements’ activity patterns relate to one another in vivo and how this changes in epileptic animals across the ictal spectrum. We predict that PV interneurons’ activity will be associated with reduced PCMEC but not PCmPFC pyramidal neuron activity in epileptiform-free states. During interictal spiking, we hypothesize that interneurons broadly are activated and that inhibition will constrain activity in both populations of pyramidal neurons during these events. We further predict that, unlike during interictal spikes, during ictal events, inhibitory neuronal firing will not be sufficient to restrain pyramidal cells, and they will be engaged even early during electrographic seizures. With continued ictal activity, we hypothesize that there will be a further breakdown in inhibitory restraint due to depolarization block in PV cells (but not other interneurons), resulting in a further increase in activity specifically in PCMEC neurons. If our hypotheses are incorrect, we gain equally valuable information about the activity patterns of these neuronal populations in chronic epilepsy. Additionally, this represents a fraction of the hypotheses testable with our data set and with future application of these methods to questions in epilepsy. We are committed to ensuring that the epilepsy community can implement these methods to address a wide range of important questions.