ORIGINAL RESEARCH article
Front. Comput. Neurosci.
Volume 19 - 2025 | doi: 10.3389/fncom.2025.1638002
This article is part of the Research TopicRealistic Multi-Scale Modeling of Neural Circuit DynamicsView all 3 articles
Dentate Gyrus Granule Cell Activation following Extracellular Electrical Stimulation: A Multi-Scale Computational Model to Guide Hippocampal Neurostimulation Strategies
Provisionally accepted
- 1University of Southern California, Los Angeles, United States
- 2University of Southern California Keck School of Medicine, Los Angeles, United States
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The effectiveness of neural interfacing devices depends on the anatomical and physiological properties of the target region. Multielectrode arrays, used for neural recording and stimulation, are influenced by electrode placement and stimulation parameters, which critically impact tissue response. This study presents a multiscale computational model that predicts responses of neurons in the hippocampus -a key brain structure primarily involved in memory formation, especially the conversion of short-term memories into long-term storage -to extracellular electrical stimulation, providing insights into the effects of electrode positioning and stimulation strategies on neuronal response. Methods: We modeled the rat hippocampus with highly detailed axonal projections, integrating the Admittance Method to model propagation of the electric field in the tissue with the NEURON simulation platform. The resulting model simulates electric fields generated by virtual electrodes in the perforant path of entorhinal cortical (EC) axons projecting to the dentate gyrus (DG) and predicts DG granule cell activation via synaptic inputs. Results: We determined stimulation amplitude thresholds required for granule cell activation at different electrode placements along the perforant path. Membrane potential changes during synaptic activation were validated against experimental recordings. Additionally, we assessed the effects of bipolar electrode placements and stimulation amplitudes on direct and indirect activation. Conclusion: Stimulation amplitudes above 750 µA consistently activate DG granule cells. Lower stimulation amplitudes are required for axonal activation and downstream synaptic transmission when electrodes are placed in the molecular layer, infra-pyramidal region, and DG crest. Significance: The study and underlying methodology provide useful insights to guide the stimulation protocol required to activate DG granule cells following the stimulation of EC 1 Sample et al.axons; the complete realistic 3D model presented constitutes an invaluable tool to strengthen our understanding of hippocampal response to electrical stimulation and guide the development and placement of prospective stimulation devices and strategies.
Keywords: extracellular electrical stimulation, Admittance method, Electrode design, multiscale modeling, Neuron
Received: 30 May 2025; Accepted: 04 Jul 2025.
Copyright: © 2025 Farzad, Wei, Bouteiller and Lazzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Shayan Farzad, University of Southern California, Los Angeles, United States
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