In the journey of human exploration of scientific mysteries, the deepest and most complex fields are not only the distant Milky Way, but also the nearby brain. How to clearly observe this' small universe 'interwoven with billions of neurons and trillions of synapses in its natural operating state has always been a huge challenge for scientists. Recently, a breakthrough achieved by the team of Academician Cheng Heping and Professor Wang Aimin from Peking University, in collaboration with Professor Wu Runlong's team from Beijing University of Information Science and Technology, has provided a key to this world-class problem - they have successfully developed a multi-color miniaturized two-photon microscope weighing only 2.6 grams, achieving high-resolution deep brain two-photon color imaging of freely moving mice for the first time, opening a "color window" for the brain. This achievement was recently published in the international academic journal Nature Methods and was specially recommended in a research brief of the same period. The reporter learned that since Cheng Heping led the national major scientific research instrument development project in 2014, the team has completed four technological iterations. From the first generation micro microscope weighing only 2.2 grams in 2017, which achieved the first level imaging of synapses in freely moving animals, to the second generation in 2021, which expanded the field of view by 7.8 times and achieved three-dimensional imaging, and to the third generation in 2023, which penetrated the deep hippocampus with the help of three photon imaging - every step embodies the wisdom and persistence of interdisciplinary cooperation. The latest fourth generation system has achieved a landmark technological breakthrough in three dimensions: multi-color excitation, deep brain imaging, and multi-scale observation. Among them, the team successfully developed a 700 to 1060 nanometer ultra wideband anti resonant hollow core fiber, which solved the limitation of traditional bandgap hollow photonic crystal fibers that only support monochromatic lasers. This innovation enables low loss and low dispersion transmission of multi wavelength femtosecond pulse lasers, laying the physical foundation for simultaneous observation of multiple cellular functional structures. As Wu Runlong said, "This is equivalent to 'color broadcasting' the dynamic activity of neurons and organelles in the brain." In the Alzheimer's disease model mouse experiment, the team successfully captured three color images of neuronal calcium signals, mitochondrial calcium signals, and amyloid plaque deposition simultaneously, and discovered mitochondrial calcium dynamics abnormalities in the early stages of the disease - this not only demonstrates the powerful function of the instrument, but also reflects its enormous potential in revealing the mechanisms of neurological diseases. In terms of deep brain imaging, the new generation of microscopes has also achieved a breakthrough. Wu Runlong introduced that through precise optical design and system level aberration correction, the team has advanced the imaging depth to 850 microns in the cortical area, which is more than three times deeper than the previous micro two-photon microscope, making it no longer a dream to observe neural activity in the deep structure of freely moving animal brains. What is even more commendable is the seamless switching ability of the system at the imaging scale. The team has innovatively designed three interchangeable autofocus objectives, which are suitable for high-resolution fine imaging, large field of view observation, and high-performance signal collection. The team members completed the objective lens replacement in just 30 seconds during the demonstration, and the real-time image on the screen immediately changed from "fine close-up" to "wide-angle panorama", truly realizing the convenient and efficient multi-scale observation of "changing the objective lens like screwing a screw". Cheng Heping said that for many years, the non-invasive deep brain imaging capability of multi-color fluorescent labeling could only be achieved on large desktop devices. The team has solved the problem of multi-color excitation imaging with miniaturized two-photon microscopes for the first time, bringing breakthrough progress to the study of complex brain networks. In the future, this technology will have broad application prospects in understanding the principles of brain cognition, studying the mechanisms of brain diseases, evaluating neuropharmaceuticals, and brain computer interfaces. (New Society)