Microglial Dynamics under Chronic Perturbation

Axis 1 and Axis 2 equal weight. A foundational thrust on microglial homeostasis and surveillance under chronic mechanical, electrical, and ultrasonic perturbation, with translational arms in neuroinflammation across MS, AD, TBI, and stroke.

Open Scientific Question

How do microglia maintain homeostasis under chronic input, and what are the temporal dynamics of microglial surveillance during sustained electrical, ultrasonic, or pharmacological perturbation? Microglial responses to acute injury are well-characterized, but the chronic dynamics that determine whether microglia transition between homeostatic surveillance and sustained inflammatory states are less understood. The lab uses parametric chronic perturbation to dissect these dynamics on timescales (minutes to months) that are not accessible in standard injury models.

Anchor Papers from the Lab

•         Preszler C, Stieger K, Chen K, Zhang G, Kozai TDY. Microglia surveillance is directed toward neuron activation during sustained intracortical microstimulation. Journal of Neural Engineering, 2026. The first demonstration that microglial surveillance dynamics during sustained ICMS are directed toward activated neurons, suggesting an active homeostatic role rather than a passive injury response.

•         Li L et al. Low-intensity pulsed ultrasound modulates microglial activation around chronically implanted neural electrodes. Nature Communications, 2024. Demonstrated that LIPUS, a non-invasive perturbation modality, modulates microglial activation around chronic implants, with implications for both neural interface longevity and neuroinflammatory disease.

•         Dubaniewicz M, Eles JR, Lam S, Song S, Cambi F, Sun J, Wellman SM, Kozai TDY. Inhibition of Na+/H+ exchanger modulates microglial activation and scar formation following microelectrode implantation. Journal of Neural Engineering, 2021. Pharmacological perturbation of microglial activation, identifying NHE as a modulatable mechanism.

•         Savya SP, Li F, Lam S, Wellman SM, Stieger KC, Chen K, Eles JR, Kozai TDY. In vivo spatiotemporal dynamics of astrocyte reactivity following neural electrode implantation. Biomaterials, 2022. Companion characterization of astrocyte dynamics, paired with the microglial work.

Disease and Translational Connections

•         Neuroinflammation in Alzheimer's disease, multiple sclerosis, traumatic brain injury, and stroke. Microglia are central effectors in all four conditions, and the lab's chronic perturbation context provides mechanism that injury and disease models cannot match in temporal resolution.

•         LIPUS as a non-invasive therapeutic modality. The Nature Communications 2024 finding establishes a translational pathway for LIPUS in neuroinflammatory disease, paired with industry collaboration through Actuated Medical.

•         Engineering implication. Microglial activation and the inflammatory cascade around chronic implants determine the foreign body response and long-term device function. Mechanism-informed strategies for modulating microglial dynamics are direct forward translation.

•         Pharmacological intervention. Targeted modulation of microglial activation through NHE inhibition, and other identified pharmacological pathways, supports forward translation to disease and device applications.

Skills Developed by Trainees on This Thrust

•         Longitudinal in vivo two-photon imaging of microglial dynamics with cell-type-specific labeling (CX3CR1-GFP, Iba1)

•         Parametric ICMS, with simultaneous imaging and electrophysiological readout

•         Low-intensity pulsed ultrasound (LIPUS) and focused ultrasound with microbubbles

•         Pharmacological intervention studies, including identification and validation of new pharmacological targets

•         Quantitative analysis of microglial morphology, process dynamics, and surveillance behavior

• Integration of microglial readouts with electrophysiology and behavioral measures