Mural Cell Function and Chronic Neurovascular Coupling

Axis 2 primary, Axis 1 secondary. A rapidly developing thrust addressing pericyte and smooth muscle cell biology around chronic implants, with implications for small vessel disease, vascular contributions to cognitive impairment, and post-stroke neurovascular unit reorganization.

Open Scientific Question

What computational and metabolic roles do mural cells (pericytes and vascular smooth muscle cells) play in adult cortical neurovascular coupling under physiological and perturbed conditions? The mural cell community has been constrained by the absence of in vivo perturbation tools that allow longitudinal manipulation and observation in adult cortex. The lab's chronic device implantation context produces a controlled, quantifiable perturbation of the local vascular bed, with simultaneous longitudinal imaging access to mural cell populations across weeks to months. This platform reveals mural cell remodeling dynamics that other in vivo preparations cannot match.

Anchor Papers from the Lab

•         Wellman SM, Forrest AM, Douglas MM, Subbaraman A, Zhang G, Kozai TDY. Dynamic changes in the structure and function of brain mural cells around chronically implanted microelectrodes. Biomaterials, 2025, 315, 122963. The field's primary characterization of mural cell remodeling around chronic implants, demonstrating that pericytes and smooth muscle cells reorganize structurally and functionally over weeks to months with consequences for local neurovascular coupling.

•         Suematsu N et al. Chronic alteration of Ca2+ and hemodynamic signals induced by intracortical microstimulation in the visual cortex of awake mice. Biomaterials, 2026. Chronic ICMS hemodynamics, demonstrating that parametric electrical stimulation produces measurable hemodynamic responses that depend on mural cell function and that drift over chronic timescales.

•         Wellman SM, Li L, Yaxiaer Y, McNamara IN, Kozai TDY. Revealing spatial and temporal patterns of cell death, glial proliferation, and blood-brain barrier dysfunction around implanted intracortical neural interfaces. Frontiers in Neuroscience, 2019, 13, 493. Established the BBB and vascular dysfunction framework that the mural cell work builds on.

•         Eles JR, Kozai TDY. In vivo imaging of calcium and glutamate responses to intracortical microstimulation. Biomaterials, 2020, 234, 119767. Linked stimulation parameters to local hemodynamic and excitatory transmitter responses.

Disease and Translational Connections

•         Small vessel disease and vascular contributions to cognitive impairment and dementia (VCID). Mural cell dysfunction is a central feature, and the lab's longitudinal in vivo characterization provides mechanism that disease models cannot match in temporal resolution.

•         Post-stroke neurovascular unit reorganization. The mural cell remodeling dynamics observed around chronic implants parallel the reorganization the post-stroke neurovascular unit undergoes during functional recovery.

•         Traumatic brain injury. Vascular and BBB dysfunction is a major contributor to long-term TBI outcome, and the lab's mural cell biology framework informs hypotheses about post-TBI vascular recovery.

•         Engineering implication. Mural cell remodeling is a previously uncharacterized determinant of chronic recording quality and chronic stimulation efficacy, with direct implications for chronic BCI longevity.

Skills Developed by Trainees on This Thrust

•         Longitudinal in vivo two-photon imaging of pericytes, smooth muscle cells, and the cortical vasculature

•         Hemodynamic readouts paired with electrophysiology, including local cerebral blood flow and intrinsic optical signal imaging

•         Finite element and biophysical modeling of stimulation field spread, vascular response, and human BCI outcomes

•         Mural cell-specific transgenic and viral targeting approaches

•         Quantitative analysis of vascular network topology and remodeling