# Real-time Aberration Sensor for Large-Scale Microscopy Deep in the Mouse and Adult Zebrafish Brain

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $1,982,304

## Abstract

ABSTRACT
Optical imaging holds tremendous promise in our endeavor to understand brain functions. The major challenges
for optical brain imaging are depth and speed. Due to optical aberrations and tissue scattering, the penetration
depth and imaging speed of optical microscopy in the brains (e.g., mouse) is limited. The constraints in depth
and speed make large-scale, deep imaging of mouse brain activity out of reach of current imaging techniques.
Hardware adaptive optics (AO) has proven to be valuable for in vivo brain imaging with two-photon microscopy
(2PM), and will have even larger impact for deep brain 3-photon microscopy (3PM); however, existing AO
techniques require iterative optimization using multiphoton excited fluorescence signal. While adequate for
imaging relatively shallow regions of the brain (< 1 mm deep), iterative optimization is impractical with ultra-deep
imaging since the fluorescence signal deceases exponentially with imaging depth. The required integration time
to obtain the necessary signal-to-noise ratio for iterative optimization becomes prohibitively long. In this program,
we will leverage the advantages provided by computational adaptive optics (CAO) in optical coherence
microscopy (OCM), specifically the strong OCT signal (from linear backscattering), and parallel computing on a
high-end graphics processing unit (GPU), to provide orders of magnitude speed-up for the sensing of
sample-induced aberrations throughout a volume of interest. A long-wavelength OCM system and CAO
aberration sensor will be utilized to drive a hardware AO system to correct depth-dependent aberrations, push
3PM imaging depth beyond currently demonstrated limits, and increase imaging speed by at least one order of
magnitude. Additionally, by combining with recently developed adaptive excitation laser technology, we will
achieve approximately 300-fold increase in photon budget, which will enable truly unprecedented 3PM imaging
speed and depth. Successful completion of this program will enable rapid aberration sensing at the depth range
of 1 to 2 mm, and will open the exciting new opportunity of recording the neural activity of the dentate gyrus of
adult mice through the intact brain. With its high-speed and deep-tissue aberration sensing capability, and zero
additional photobleaching and phototoxicity, our novel method for real-time aberration sensing and correction is
ideally positioned to transform our ability for large-scale, deep recording of mouse and adult zebrafish brain
activity. This imaging approach will significantly extend the information available for neuroscience studies on
individual cell-cell as well as circuit interactions that underlie normal and diseased brain function. The technology
developed by this proposal will be applicable to imaging in other biological systems where large-scale, deep
imaging at high spatiotemporal resolution is needed.

## Key facts

- **NIH application ID:** 10166305
- **Project number:** 1R01NS120819-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Steven Graham Adie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,982,304
- **Award type:** 1
- **Project period:** 2021-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166305

## Citation

> US National Institutes of Health, RePORTER application 10166305, Real-time Aberration Sensor for Large-Scale Microscopy Deep in the Mouse and Adult Zebrafish Brain (1R01NS120819-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10166305. Licensed CC0.

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