A team of engineers and neuroscientists has demonstrated for the first time that human brain organoids implanted in mice make functional connections to the animals’ cortex and respond to external sensory stimuli. The implanted organoids responded to visual stimuli in the same way as the surrounding tissues; This is an observation the researchers were able to make in real time over several months, thanks to an innovative experimental setup combining transparent graphene microelectrode arrays and two-photon imaging.
The team, led by Duygu Kuzum, a faculty member in the Department of Electrical and Computer Engineering at the University of California San Diego, details their findings in the December 26 issue of the journal. Nature Communication. Kuzum’s team collaborated with researchers from Anna Devor’s lab at Boston University; Alysson R. Muotri’s lab at UC San Diego; and Fred H. Gage’s lab at the Salk Institute.
Human cortical organoids are usually derived from human induced pluripotent stem cells, which themselves are derived from skin cells. These brain organoids have recently emerged as promising models for studying human brain development and a range of neurological conditions.
But until now, no research team had demonstrated that human brain organoids implanted in the mouse cortex can share the same functional properties and respond to stimuli in the same way. This is because the technologies used to record brain functions are limited and cannot record activity that usually only lasts a few milliseconds.
The UC San Diego-led team succeeded in solving this problem by developing experiments combining microelectrode arrays made of transparent graphene and two-photon imaging, a microscopy technique that can image living tissue down to a millimeter thick.
First author of the article and Ph.D. Student in Kuzum’s research group at UC San Diego. “Our experiments reveal that visual stimuli evoke electrophysiological responses in organoids that match those from the surrounding cortex.”
The researchers hope that this combination of innovative neural recording technologies to study organoids will serve as a unique platform to comprehensively evaluate organoids as models for brain development and disease and to explore their use as neural prosthesis to restore function of lost, degenerated or damaged brain regions. . .
“This experimental setup offers unprecedented opportunities for investigating human neural network-level dysfunctions that underlie developmental brain diseases,” said Kuzum.
Kuzum’s lab first developed the transparent graphene electrodes in 2014 and has been advancing the technology ever since. The researchers used platinum nanoparticles to reduce the impedance of graphene electrodes by a factor of 100 while keeping them transparent. Low-impedance graphene electrodes can record and display neuronal activity at both the macro-scale and single-cell levels.
By placing an array of these electrodes on the transplanted organoids, the researchers were able to electrically record, in real time, neural activity from both the implanted organoid and the surrounding host cortex. Using two-photon imaging, they also observed mouse blood vessels growing towards the organoid, which supplies the implant with essential nutrients and oxygen.
The researchers administered a visual stimulus – an optical white light LED – to mice with implanted organoids while the mice were under two-photon microscopy. They observed electrical activity in the electrode channels on the organoids, indicating that the organoids responded to the stimulus in the same way as the surrounding tissue. Electrical activity emitted through functional connections from the area closest to the visual cortex in the area of implanted organoids. In addition, the low-noise transparent graphene electrode technology enabled electrical recording of sudden activity from the organoid and surrounding mouse cortex. Graphene recordings showed increases in the power of gamma oscillations and phase locking of spikes from organoids to slow oscillations from mouse visual cortex. These findings suggest that the organoids establish synaptic connections with surrounding cortex tissue and receive functional input from the mouse brain three weeks after implantation. The researchers continued these chronic multimodal experiments for eleven weeks and demonstrated the functional and morphological integration of implanted human brain organoids with the host mouse cortex.
Next steps include incorporating calcium imaging into the experimental set to visualize spike activity in organoid neurons, alongside longer experiments involving models of neurological disease. Other methods can be used to monitor axonal projections between the organoid and mouse cortex.
“More down the road, we envision this combination of stem cells and neural recording technologies will be used to model disease under physiological conditions, to study candidate treatments on patient-specific organoids, and to evaluate the potential of organoids to restore certain lost, degenerated or damaged ones.” brain regions,” said Kuzum.
The study was funded by the National Institutes of Health and the Norwegian Research Council and the National Science Foundation.
materials provided by University of California – San Diego. Originally written by Ioana Patringenaru. Note: Content can be edited for style and length.