Investigation of block phenomena in pyramidal, cochlear, and retinal neurons

Abstract

Selective stimulation with microelectrodes of individual neurons is a major challenge in neuroprosthetics. Actively propagation of action potential (AP) is possible within a stimulation window with a lower (LT) and an upper (UT) threshold. An anodal surround block inhibits AP propagation during an intensive cathodic stimulus by hyperpolarizing the flanks in the axonal membrane. A somatic block, in contrast, stops generating AP in the soma caused by a reversal sodium current at strong depolarizations. An interval between stimulating and blocking states is of concern in neuronal excitation. Here, the threshold window and block phenomena of pyramidal (PC), cochlear (SGC), retinal (RGC) neurons, as well as myelinated and non-myelinated axons were analyzed. 3D models of neurons were simulated as cable models leading to large systems of ordinary differential equations, solved with numerical solutions, e.g., backward Euler, MATLAB ODE, and CVODE in Neuron. The point source approach was applied to calculate the extracellular voltage distribution in most parts except the first part, which employs a finite element method. In most calculations (with some exceptions), a monophasic cathodic pulse with a duration of 100 μs was used to investigate the threshold windows. In the first part, 3D human cochlear neurons were investigated; the main findings were: (i) 3D pathways irregularities caused significant changes in excitation profiles compared with previous 2D investigations concerning AP initiation sites and latencies which might be of interest for cochlear implant users, and (ii) increasing degeneration level caused lower anodic thresholds or anodic sensitivity. In the second part, the comparison of excitation and blockage of 2D PC, SGC, and RGC models showed the following key results: (i) Due to low sodium conductivity in the PC model, the soma was not excitable for short pulse durations. (ii) Profound degenerated SGC (soma with one layer of myelin) was not excitable at the electrode to soma distances less than 4 μm. (iii) Stimulation in close distances to soma was ruled by somatic region, and the cell UT was due to somatic block, whereas at distant stimulation, axons governed the cell excitability, and UT was due to anodal surround block. (iv) In the whole-cell experiment, the highest UTs and threshold ratios were found in the PC model for both pulse durations. In the next step, stimulation windows and block were studied in detailed reconstructed 3D morphologies of PCs (n=8), including the complex structure of axon collaterals and RGCs (n=34) for an increasing range of electrode to cell distances for positions in the soma vicinity. The main findings were: (i) Soma played almost no role in PC excitation. In contrast, for stimulating RGCs in the soma vicinity, soma may mostly rule the cell excitation, and at these distances, UT occurs due to somatic block in RGC. (ii) At LT levels, APs always initiated at axon initiation segment (AIS) in both cell types; in cells with short AIS, the AP site was close to the distal part of AIS, whereas, in cells with longer AIS, the initiation site shifted towards the center of AIS. (iii) PCs possessed extremely high UTs, and (iv) no complete block was observed in PCs. (v) The arrangement of axon collaterals in PCs significantly impacted UTs while almost no impact on LTs. The last chapter was a pure axon study comparing thin vs. thick and myelinated vs. non-myelinated fibers. Findings were: (i) LTs and UTs were higher in thin axons for myelinated and non-myelinated fibers. (ii) Increasing pulse duration leads to lower UTs and lower threshold ratios (UT/LT). (iii) Myelinated axons possessed extremely higher UTs and threshold ratios, specifically when short pulses stimulate thin axons. In summary, as previously found, axons are the most excitable parts of the cell that rule the cell excitation except for electrode positions very close to the soma. Although stimulating thick fibers are easier, it is rather challenging because of small threshold windows due to lower UTs and may lead to easier blockage situation.