Closed-loop Control of Inhibitory Theta Phase Locking Influences Seizure Activity and Cognition in a Mouse Model of Chronic Temporal Lobe Epilepsy
Abstract number :
2.056
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2022
Submission ID :
2204361
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Zoe Christenson Wick, PhD – Icahn School of Medicine at Mount Sinai; Paul Philipsberg, MS – Graduate Student, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai; Sophia Lamsifer, BA – Research Assistant, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai; Tristan Shuman, PhD – Assistant Professor, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai
Rationale: The precise timing of single-unit spiking relative to network-wide oscillations (i.e., phase locking) has long been thought to maintain excitatory-inhibitory homeostasis and coordinate cognitive processes. We recently found that epileptic mice with spontaneous seizures and cognitive deficits show altered inhibitory theta phase locking in the dentate gyrus, but the causal influence of this phenomenon has never been determined. Thus, we aimed to causally test the hypothesis that inhibitory theta phase locking can bidirectionally control seizures and cognitive performance in control and epileptic mice.
Methods: To test these hypotheses, we developed a low-latency closed-loop optogenetic system to bidirectionally control inhibitory phase locking to theta in head-fixed control and pilocarpine-treated epileptic mice navigating a virtual track. Using opto-tagging strategies, we first identified the preferred firing phase of parvalbumin+ and somatostatin+ dentate interneurons in control and epileptic mice. We then applied our closed-loop system to lock the spiking of these dentate interneurons to their preferred or non-preferred phase of theta while measuring seizure activity and accuracy of navigation.
Results: Using our closed-loop optogenetic system in awake behaving mice, we have succeeded in precisely altering the phase locking of hippocampal interneurons and we have preliminary evidence that there is a cell-type specific deficit in phase locking of parvalbumin+ dentate interneurons. We have also found evidence suggesting that, in epileptic mice, re-aligning inhibitory spiking to the preferred phase of theta diminishes seizure activity compared to stimulating at a non-preferred phase of theta. Further preliminary data show that precise theta phase locking of dentate gyrus inhibitory neurons may influence performance on a demanding dentate-dependent navigation task.
Conclusions: Theta phase locking of inhibitory spiking likely plays an important and causal role in two of the most concerning elements of epilepsy: seizures and cognitive deficits. Gaining deeper insights into the impacts of inhibitory theta phase locking may reveal its potential as an epilepsy therapeutic uniquely capable of treating both seizures and cognitive deficits.
Funding: NIH F32NS116416, CURE Taking Flight Award
Neurophysiology