Closed-Loop Control of Inhibitory Spike Timing in a Mouse Model of Chronic Temporal Lobe Epilepsy
Abstract number :
3.034
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2021
Submission ID :
1826533
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:55 AM
Authors :
Zoé 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 - Research Assistant, City University of New York Hunter College; Tristan Shuman, PhD - Assistant Professor, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai
Rationale: The precise timing of neuronal spiking relative to the brain’s endogenous oscillations (i.e., phase locking) has long been hypothesized to coordinate cognitive processes and maintain excitatory-inhibitory homeostasis, though it has never been causally tested. In the pilocarpine mouse model of chronic temporal lobe epilepsy, dentate gyrus interneurons have less accurate phase locking to hippocampal theta in epileptic mice compared to controls (Shuman et al, Nat Neuro 2020). We predict that this loss of inhibitory phase locking to theta may prevent maintenance of excitatory-inhibitory homeostasis, and thus exacerbate pathological epileptic activity. Further, we predict this loss of inhibitory phase locking to theta may prevent effective information transfer between regions, impairing performance on hippocampal-dependent cognitive tasks.
Methods: To test these hypotheses, we developed a closed-loop optogenetic system to control the phase locking of interneurons to ongoing endogenous oscillations. We performed in vivo silicon probe recordings in head-fixed control and epileptic mice navigating a virtual track, identified the baseline phase preference of parvalbumin- or somatostatin-expressing interneurons within the hippocampus, and applied our closed loop system to phase-lock their spiking to the trough or peak of hippocampal theta.
Results: This closed-loop system uses real-time signal processing to detect the target phase and deliver stimulation within milliseconds; it is capable of targeting any phase of theta with high precision. Using this system in awake behaving mice, we have succeeded in precisely altering the phase locked firing of hippocampal interneurons and have preliminary data suggesting that altering the phase locking of inhibitory neurons may mediate epileptiform activity.
Conclusions: This closed-loop system outperforms existing tools and will enable us to continue investigating the causal role of precise single-unit phase locking to network-wide oscillations. Future experiments will apply this tool to investigate the causal role of precise timing of interneuron spiking in seizure susceptibility and hippocampal-dependent cognition in the healthy and epileptic brain.
Funding: Please list any funding that was received in support of this abstract.: NIH F32NS116416 (to ZCW), CURE Taking Flight Award (to TS).
Basic Mechanisms