Dentate gyrus granule cell activation following extracellular electrical stimulation: a multi-scale computational model to guide hippocampal neurostimulation strategies

Abstract

Introduction: 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 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: admittance method; electrode design; extracellular electrical stimulation; multiscale modeling; neuron.

Figure 1

(A) Illustration depicting electrical stimulation of the hippocampal region with a diagram of the hippocampo-entorhinal circuit, illustrating the main trisynaptic pathway EC → DG → CA3 → CA1. CA, cornu ammonis; DG, dentate gyrus; EC, entorhinal cortex. (B) Serial tracing of high-resolution thin histological sections of a rat brain (Ropireddy et al., 2012) has been converted into (C) the three-dimensional voxel grid which is utilized as the tissue model in the AM-NEURON multiscale simulation, enabling detailed computational modeling of neuronal activity within this anatomically accurate hippocampal tissue model. Experimentally obtained resistivity values are applied to cell body regions (blue) and molecular layers (remaining of the model space, not shown) of DG (López-Aguado et al., 2001).

Figure 2

A granule cell compartmental model is depicted as a cable model, with compartments linked in series or parallel based on their morphology (A, B). Each compartment is modeled as a circuit. (C) This diagram illustrates how the neuron compartmental model is integrated in the tissue simulated with the Admittance Method. Notably, this diagram shows the simple case where the two (teal and orange) compartments perfectly align with nodes of the voxeled AM model. In reality, compartments may reside at arbitrary positions within the computational volume. In such cases, the voltages from surrounding nodes are used to interpolate the extracellular potential to be applied at the exact position of each compartment; (D) illustrates the circuit equivalent representation of a two-compartment neuron model.

Figure 3

2D to 3D Mapping steps and axon arbor reconstruction. (A) The 2D locations of the granule cells for all entorhinal cortex (EC) axons were obtained from experimental work by (Gaarskjaer, 1978), with each axon having ~2,500 connections, (B) B-splines were used to map the 2D data onto a 3D model, (C) Reconstruction Using ROOTS Algorithm: Reconstructed axon arbors using the ROOTS Algorithm, ensuring accurate representation of axonal paths (Bingham et al., 2020), (D) Synaptic Connections: Over 1,900 axons make synaptic connections to a single granule cell. The two depicted axons illustrate the range of dentate gyrus (DG) coverage, representing the first and last EC axons connecting to the same granule cell.

Figure 4

Stimulation locations in the 3D model: (A) Infrapyramidal, (B) Crest, and (C) Suprapyramidal. A biphasic, charge-balanced, and square-wave impulse of 1 ms width was applied to evaluate the activation of EC axons that consequently leads to synaptic activation of GC.

Figure 5

Characterization of dendritic integration of synaptic inputs in granule cells (GCs) and corresponding GC activation threshold. The plots depict the relationship between the number of active synaptic inputs and the probability of generating an action potential. Notably, the number of dendrites on which these active synapses are distributed influences the activation threshold, with more distributed configurations (i.e., increased number of dendrites) resulting in a slight decrease in the number of active synapses needed to generate an action potential. (A) Illustrates the synaptic connections of EC axons to GC at the medial perforant path (MPP), while (B) illustrates the situation where active synaptic connections are located at the lateral perforant path (LPP).

Figure 6

Comparison of intracellular voltages recorded experimentally and with our computational model. (A) illustrates the membrane potential response of our GC model at the soma and in a proximal dendrite. For this result, we used 1,800 synaptic inputs distributed on 20 dendrites. (B) shows the corresponding experimental activation profiles reported by Krueppel et al. (2011). The intracellular voltage traces obtained with the model are in accordance with experimental recordings, indicating that our simulated GC model replicates the response of its biological counterpart, highlighting the model's ability to accurately predict the cell's behavior.

Figure 7

Stimulation effects with the electrode placed in the cell body layer of the dentate gyrus at different positions. (A) shows the stimulation at the Crest, (B) at the Infra-pyramidal, and (C) at the Supra-pyramidal region. The stimulation amplitude ranges from 50 to 750 μA. The green area on the plot represents the amplitudes at which the EC synaptic connections with GCs reach a threshold, resulting in the firing of the GCs. In addition to highlight the effect of stimulation amplitude, this figure illustrates how electrode placement within these specific regions influences the activation of neural tissue in the dentate gyrus.

Figure 8

Direct and indirect (i.e., synaptic) consequences of electrical stimulation when the electrode is placed in the Molecular Layer of the Dentate Gyrus at three different positions, with different stimulation amplitudes. (A) shows the stimulation at the Crest, (B) at the Infra-pyramidal, and (C) at the Supra-pyramidal region. The stimulation amplitude ranges from 50 to 750 μA. The Y axis represents the number of axons activated. The green area on the plot represents the amplitudes at which the EC synaptic connections with GC reach a threshold, resulting in the firing of the GC.