"See through" the brain! Chinese scientists "new" super microscope

Author: Shi Xiangqi and Li Chuanfu

Imagine that when you are immersed in a wonderful film or TV show, how do hundreds of millions of neurons in your brain quickly become active and interact with each other to form special neural circuits? How do these complex neural networks generate consciousness? If the brain is accidentally hit, how do immune cells respond quickly and where do they start to rush to the affected area? Starting from cell abnormalities, what is the complete process of a tumor's development?

In order to find the answers to the above questions, the team led by Academician Dai Qionghai of Tsinghua University has brought us an unprecedented tool - the super microscope RUSH3D. The advent of this microscope marks an important step forward in the mesoscopic scale that connects the microscopic and macroscopic worlds. Researchers can now observe the interactive behaviors of large-scale and diverse cells in living mammalian tissues in a panoramic, dynamic and long-term manner, and explore the magnificent mysteries of these life activities.

Super microscope RUSH3D. Photo courtesy of Tsinghua University

Recently, Dai Qionghai's team published their research results in the top international journal Cell, announcing the launch of a new generation of mesoscopic in vivo microscopy instrument RUSH3D. This achievement not only fills the gap in the international mesoscopic in vivo three-dimensional observation of mammals, but also provides a new perspective for the study of complex biological processes.

Although traditional optical microscopes can focus on the material interaction process within a single cell, they are often limited by the inherent contradiction between field of view and resolution when observing living tissues. The emergence of RUSH3D allows researchers to dynamically observe the tissue heterogeneity of mammalian organ scale subcellular precision in a panoramic manner for the first time. This allows in situ study of the dynamic interaction behavior of large-scale diverse cells in complete physiological and pathological processes in living tissues, with unprecedented spatial and temporal cross-scale imaging capabilities.

Super microscope RUSH3D imaging effect. Photo courtesy of Tsinghua University

This technological breakthrough is due to the unremitting efforts of Academician Dai Qionghai's team over the years. As early as 2013, they began research in the field of mesoscopic in vivo microscopy. In 2018, they successfully developed the world's first billion-pixel mesoscopic fluorescence microscope RUSH, which was hailed by international peers as a pioneer in the field of mesoscopic microscopy. However, the RUSH system still faced a series of technical bottlenecks at the time, including how to use two-dimensional sensors to achieve high-speed three-dimensional imaging, how to avoid cell damage caused by long-term laser irradiation, how to overcome optical aberrations and background interference caused by complex imaging environments, how to improve the imaging signal-to-noise ratio under weak light conditions, and how to efficiently process large-scale mesoscopic data.

In the next six years, Academician Dai Qionghai's team continued to tackle key problems and proposed key theories and technologies such as scanning light field imaging principles, digital adaptive optics architecture, virtual scanning algorithm, confocal scanning light field architecture, and self-supervised denoising algorithm. They solved a series of barriers in mesoscopic in vivo microscopy imaging one by one and laid the foundation for the advent of a new generation of mesoscopic in vivo microscopy instrument RUSH3D.

Super microscope RUSH3D fills the technological gap. Photo courtesy of Tsinghua University

The advent of RUSH3D has not only achieved a major breakthrough in technology, but also demonstrated great potential in practical applications. In the field of brain science, RUSH3D can perform long-term high-speed three-dimensional imaging of the entire brain of awake mice that are "watching a movie", and with sufficient spatial resolution, present the neuronal networks that shine like stars in the sky in the 17 brain regions observed. This provides strong support for exploring the principles of brain functions such as biological intelligence and consciousness, as well as promoting research on brain degenerative diseases, and further promotes the exploration of brain-inspired artificial intelligence. In the field of immunology, RUSH3D observed for the first time the cellular-level immune response in multiple brain regions after acute brain injury, and found the migration and reflux of a large number of neutrophils from non-vascular areas to the brain, providing a new perspective for immunology research.

This achievement of Academician Dai Qionghai's team is not only a demonstration of my country's scientific research strength, but also an important contribution to human exploration of the mysteries of life. Their efforts have enabled us to have a deeper understanding of the brain and get closer to the mysteries of life. In the future, we have reason to believe that with the continuous application and development of advanced instruments such as RUSH3D, human cognition of life will reach a new height. Let us look forward to these super microscopes being able to reveal more secrets about life for us and bring more hope to human health and well-being.