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Deep-tissue high-sensitivity multimodal imaging and optogenetic manipulation enabled by biliverdin reductase knockout

Author

Listed:
  • Ludmila A. Kasatkina

    (Albert Einstein College of Medicine)

  • Chenshuo Ma

    (Duke University)

  • Huaxin Sheng

    (Duke University)

  • Matthew Lowerison

    (Duke University
    University of Illinois Urbana-Champaign)

  • Luca Menozzi

    (Duke University)

  • Mikhail Baloban

    (Albert Einstein College of Medicine)

  • Yuqi Tang

    (Duke University)

  • Yirui Xu

    (Duke University)

  • Lucas Humayun

    (Duke University)

  • Tri Vu

    (Duke University)

  • Pengfei Song

    (Duke University
    University of Illinois Urbana-Champaign)

  • Junjie Yao

    (Duke University)

  • Vladislav V. Verkhusha

    (Albert Einstein College of Medicine
    University of Helsinki)

Abstract

Performance of near-infrared probes and optogenetic tools derived from bacterial phytochromes is limited by availability of their biliverdin chromophore. To address this, we use a biliverdin reductase-A knock-out mouse model (Blvra−/−), which elevates endogenous biliverdin levels. We show that Blvra⁻/⁻ significantly enhances function of bacterial phytochrome-based systems. Light-controlled transcription using iLight optogenetic tool improves ~25-fold in Blvra−/− cells, compared to wild-type controls, and achieves ~100-fold activation in neurons. Light-induced insulin production in Blvra−/− mice reduces blood glucose by ~60% in diabetes model. To overcome depth limitations in imaging, we employ 3D photoacoustic, ultrasound, and two-photon fluorescence microscopy. This enables simultaneous photoacoustic imaging of DrBphP in neurons and super-resolution ultrasound localization microscopy of brain vasculature at depths of ~7 mm through intact scalp and skull. Two-photon microscopy achieves cellular resolution of miRFP720-expressing neurons at ~2.2 mm depth. Overall, Blvra−/− model represents powerful platform for improving efficacy of biliverdin-dependent tools for deep-tissue imaging and optogenetic manipulation.

Suggested Citation

  • Ludmila A. Kasatkina & Chenshuo Ma & Huaxin Sheng & Matthew Lowerison & Luca Menozzi & Mikhail Baloban & Yuqi Tang & Yirui Xu & Lucas Humayun & Tri Vu & Pengfei Song & Junjie Yao & Vladislav V. Verkhu, 2025. "Deep-tissue high-sensitivity multimodal imaging and optogenetic manipulation enabled by biliverdin reductase knockout," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61532-4
    DOI: 10.1038/s41467-025-61532-4
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