The researchers developed experiments that combine microelectrode arrays made from transparent graphene, and two-photon imaging, a microscopy technique that can image living tissue up to one millimeter in thickness. Credit: David Baillot/UC San Diego
Key Points:
- For the first time, researchers showed organoids respond to external sensory stimuli.
- The key was innovative recording technology—an experimental setup that combined transparent graphene microelectrode arrays and two-photon imaging.
- Next, the team will look to record longer experiments involving neurological disease models.
A team of engineers and neuroscientists from UC San Diego has demonstrated for the first time that human brain organoids implanted in mice have established functional connectivity to the animals’ cortex and responded to external sensory stimuli. The implanted organoids reacted to visual stimuli in the same way as surrounding tissues.
The first-of-its-kind observation was made possible with the development of an experimental setup that combines transparent graphene microelectrode arrays and two-photon imaging.
Previously, no research team had been able to demonstrate that human brain organoids implanted in the mouse cortex were able to react to stimuli. This is because the technologies used to record brain function are limited, and are generally unable to record activity that lasts just a few milliseconds.
The UC San Diego-led team was able to solve this problem by developing experiments that combine microelectrode arrays made from transparent graphene, and two-photon imaging, a microscopy technique that can image living tissue up to 1 millimeter in thickness.
For the study, published in Nature Communications, the team applied a visual stimulus—an optical white light LED—to the mice with implanted organoids while they were under two-photon microscopy. The scientists observed electrical activity in the electrode channels above the organoids, showing that the organoids were reacting to the stimulus in the same way as surrounding tissue. The electrical activity propagated from the area closest to the visual cortex in the implanted organoids area through functional connections.
At the same time, the low-noise transparent graphene electrode technology enabled electrical recording of spiking activity from the organoid and the 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.
The researchers say the findings suggest that the organoids had established synaptic connections with surrounding cortex tissue three weeks after implantation, and received functional input from the mouse brain. They continued these chronic multimodal experiments for 11 weeks and showed functional and morphological integration of implanted human brain organoids with the host mice cortex.
The team says their next steps include longer experiments involving neurological disease models, as well as incorporating calcium imaging in the experimental set up to visualize spiking activity in organoid neurons. Other methods could also be used to trace axonal projections between organoid and mouse cortex.
Information provided by UC San Diego.