Abstract Objective: Intracortical microstimulation (ICMS) is a widely used tool for neuroprostheses, but its long-term efficacy is often limited by foreign body response and neuroinflammatory responses at the electrode-tissue interface. Microglia orchestrate neuroinflammation and regulate synaptic plasticity, and low-frequency stimulation has been shown to promote anti-inflammatory microglial phenotypes. Approach: We investigated how 10-Hz ICMS influences microglia-neuron interactions during the first three days post-implantation using in vivo two-photon imaging in Cx3cr1-GFP/jRGECO1a mice. Microglial motility, morphology, and process orientation were tracked relative to electrode placement and neuronal calcium activity (measured as change in fluorescence, ΔF/F). Main Results: A one-hour session of 10-Hz ICMS did not induce overt classical morphological activation of microglia but robustly increased process motility, with extensions dynamically tracking neurons showing early activation or subsequent functional suppression. By post-implantation Day 2, microglial processes were significantly more likely to engage neurons with high early calcium responses after stimulation onset (mean orientation angle: 74.3° ± 11.8°), but this engagement shifted during prolonged stimulation (117.0° ± 9.2°, p = 0.0017), indicating context-dependent interactions. Contact frequency scaled with neuronal adaptation profiles, and neurons exhibiting depressed activity received the most contacts immediately after implantation (1.2 ± 0.3 contacts, p = 0.046). Significance: These findings reveal stimulus-associated, neuron-dependent surveillance behaviors of microglia during early post-implantation ICMS and suggest that microglia actively participate in short-term modulation of stimulated cortical circuits.
Preszler et al. (Mon,) studied this question.