Unveiling Molecular Diffusion in the Brain with Multidimensional Single-Particle Localization Microscopy

Speaker: Laurent COGNET

Venue: Room 215, No. 8 Hainayuan Building, Zijingang Campus

Abstract: Single-molecule localization microscopy (SMLM) has set a new paradigm in optical imaging, providing access to structural and dynamic processes at the nanoscale, well beyond the diffraction limit. Yet, extending SMLM from isolated cells to complex, intact biological tissues remains challenging, notably because of the limited brightness of fluorescent emitters and poor light penetration at visible wavelengths.

To circumvent these limitations, we developed a framework combining SMLM with single-wall carbon nanotubes luminescing in the short-wave infrared (SWIR). Tracking individual nanotubes enables the extracellular space (ECS) of intact live brain tissues to be mapped and explored at the nanoscale, including in the context of neurodegenerative diseases. Building on this strategy, I will present how a toolbox of SWIR nanoprobes, advanced optical modalities, and analytical methods can reveal the complexity of diffusion processes in the brain ECS. Our recent measurements preformed in 3D uncover the scale-dependent emergence of hindered diffusion, providing new insights into the physical organization and transport properties of this complex medium. Finally, single-particle orientation tracking of ultrashort nanotubes allows local viscosity and spatial tortuosity to be disentangled, revealing rheological features inaccessible through translational diffusion analysis alone.