Chris Xu
Cornell University, NY·Biomedical Engineering
Light can show individual brain cells at work, but brain tissue scatters light so strongly that most microscopes cannot see more than a fraction of a millimeter below the surface. Multiphoton microscopy partly solves this.
- Fields
Biomedical Engineering
Engineering
Neuroscience
- Topics
three-photon microscopy
two-photon microscopy
multiphoton microscopy
- Grants
- 4 known grants, through Jun 2030
What they work on
- Raise the three-photon fluorescence signal by about 10,000-fold through new lasers and imaging techniques, to image mouse brain activity with sub-cellular resolution at about 2 mm depth.
- Design, fabricate and validate a bifocal catadioptric objective, a lens built from both mirrors and glass, that performs two-photon imaging of shallow layers and three-photon imaging of deep layers of mouse brain at the same time.
- Boost fluorescence collection about 5-fold beyond commercial objectives at depths over 1 mm, and combine the new lens with focus-tunable lenses for fast volume imaging across about 1.2 mm.
- Build a 1300 nm adaptive excitation source, a laser that fires pulses only within chosen regions of interest, and integrate it with high-speed scanners for random-access three-photon microscopy.
- Test the adaptive-laser three-photon system in three proof-of-concept animal experiments that address key neuroscience problems.
- Develop a next-generation three-photon microscope with about 100-fold better performance, multi-color imaging from a single wavelength and a low-cost fiber laser, and demonstrate it in organs beyond the brain.
More about the research
It uses intense, short laser pulses so that a fluorescent molecule glows only when it absorbs two or three photons at once, which happens only at the focus. Two-photon microscopy (2PM) at 920 nm reaches about 0.7 mm into the mouse brain when imaging activity with GCaMP, a protein that glows when neurons fire. Three-photon microscopy (3PM) at 1300 nm reaches about 1.1 mm. The grants argue that 3PM could, in principle, reach about twice that depth. Across four projects, the lab builds new lasers, lenses and imaging methods to make 3PM deeper, faster, cheaper and more widely used.
Why it matters
Deeper, faster imaging inside living tissue could let neuroscientists watch neurons in deep brain layers that no current optical method can reach, in intact animals. The grants also name immunology and cancer biology as fields that need high-resolution imaging deep within organs. A cheaper fiber-based laser and work with industry partners could bring three-photon microscopes into ordinary biomedical labs, much as two-photon microscopes spread in earlier decades.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Jian-Young Wu
Georgetown University, DC·Neuroscience
Test whether patterned pinhole illuminators, built from glass-disk pinhole patterns or microlens arrays, reduce background light and strengthen calcium signals in brain tissue densely labeled with the calcium sensor GCaMP6f.
David Tank
Princeton University, NJ·Neuroscience
Identify which task features (active navigation, passive navigation, or visual stimulation) produce sequential neural activity, by recording from relevant mouse brain regions during tasks that isolate each feature.
Mark Siemens
University of Denver, CO·Physics
Develop DeepSpiral, a super-resolution microscope that combines multiphoton excitation with single-molecule localization microscopy to image molecules at the nanometer scale up to 300 microns deep in living brain tissue.
The school
Cornell University: 37 labs on PI Pages, $1.6B a year on research, 537 research doctorates a year.
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