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<p>Performance of near-infrared probes and optogenetic tools derived from bacterial&#xa0;phytochromes is limited by availability of their biliverdin chromophore. To address this, we use a biliverdin reductase-A knock-out mouse model (Blvra<sup>−/−</sup>), which elevates endogenous biliverdin levels. We show that Blvra⁻/⁻ significantly enhances function of bacterial&#xa0;phytochrome-based systems. Light-controlled transcription using iLight optogenetic tool improves ~25-fold in Blvra<sup>−/−</sup> cells,&#xa0;compared to wild-type controls, and achieves ~100-fold activation in neurons. Light-induced insulin production in Blvra<sup>−/−</sup> mice reduces blood glucose by ~60% in diabetes model. To overcome depth limitations in imaging, we employ 3D photoacoustic, ultrasound, and two-photon fluorescence&#xa0;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<sup>−/−</sup> model represents powerful platform for improving efficacy of biliverdin-dependent tools for deep-tissue imaging and optogenetic manipulation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月14日

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  • 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. Verkhusha

摘要

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.