For the First Time, Human Brain Organoids Implanted in Mice Show Response to Visual Stimuli

For the First Time, Human Brain Organoids Implanted in Mice Show Response to Visual Stimuli ...

Researchers at UC San Diego developed microelectrode arrays made from transparent graphene, as well as two-photon imaging, a microscopy technique that can photograph living tissue up to one millimeter thick.

For the first time, a group of engineers and neuroscientists have demonstrated that brain organoids implanted in mice make functional connections to the mice's cortex and respond to external sensory stimuli similarly to the surrounding tissues, thanks to a transparent graphene microelectrode array and two-photon imaging system that allowed for real-time monitoring.

Duygu Kuzum, a professor in UC San Diego's electrical and computer engineering department, was the lead author of the research, which has recently been published in the journal Nature Communications. Other collaborators include researchers from Anna Devor's lab at Boston University, Alysson R. Muotri's lab at the Salk Institute.

Madison Wilson, a Ph.D. student at UC San Diego, is the first author of a research that shows that human brain organoids implanted in mice have established functional connectivity to the animals' brain and have responded to external sensory stimuli.

Human cortical organoids are made up of human induced pluripotent stem cells, which are usually derived themselves from skin cells. These brain organoids have recently emerged as promising models to study the development of the human brain as well as a wide spectrum of neurological conditions.

No research team has been able to demonstrate that human brain organoids implanted in the mouse cortex could have the same functional properties and respond to stimuli in the same way until now. This is because the methods used to record brain function are limited, and are generally incapable of recording activity that lasts only a few milliseconds.

The researchers examined electrical activity in the electrode channels above the organoids, revealing that the organoids responded to the stimulus in the same manner as the surrounding tissue. Credit: David Baillot

This problem was solved by a UC San Diego-led team who combined microelectrode arrays made from transparent graphene with two-photon imaging, a microscopy technique that can image living tissue up to a millimeter in thickness.

Madison Wilson, the paper's first author and a Ph.D. student in Kuzum's research group at UC San Diego, explains that visual stimulation induces electrical reactions in the organoids, comparable to responses from the surrounding cortex.

The researchers anticipate that this unique set of neural recording techniques to investigate organoids will provide a unique platform to comprehensively evaluate organoids as models for brain development and disease, and investigate their use as neural prosthetics to restore function to degenerated or damaged brain regions.

Researchers were able to detect and see the connection between a transplanted human brain organoid and a mouse brain. Credit: Madison Wilson/UC San Diego

"This experimental setup opens up unprecedented possibilities for investigations into the causes of developmental brain disorders at the human neural network," according to Kuzum.

Kuzum's lab first developed the transparent graphene electrodes in 2014, and has been continuously improving the technology since. The researchers used platinum nanoparticles to reduce the impedance of graphene electrodes by 100 times while keeping them transparent.

Researchers were able to observe neural activity from both the implanted organoid and the surrounding host cortex in real-time by placing an array of these electrodes on the organoid.

Researchers measured organoids in mice that had implanted organoids using an optical white light LED. They observed electrical activity in the electrode channels above the organoids, indicating that the organoids were responding to the stimulus in the same manner as the surrounding tissue.

The low-noise transparent graphene electrode technology enabled the recording of spiking activity from the organoid and the surrounding mouse visual cortex. These 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.

Longer experiments with neurological disease models may be considered in the future, as well as incorporating calcium imaging in the experimental setup to visualize spiking activity in organoid neurons. Other techniques may be employed to trace axonal projections between organoid and mouse cortex.

"We anticipate that this combination of stem cells and neurorecording technologies will be used to model disease under physiological conditions, investigating candidate therapies on patient-specific organoids, and evaluating organoids' ability to restore specific lost, degenerated, or damaged brain regions," Kuzum said.

Madison N. Wilson, Martin Thunemann, Yichen Lu, Francesca Puppo, Jeong-Hoon Kim, Srdjan Djurovic, Ole A. Andreassen, Fred H. Gage, Anna Devor, and Duygu Kuzum, 26 December 2022, Nature Communications. DOI: 10.1038/s41467-022-35536-3

The National Institutes of Health and the Norwegian Research Council have contributed to the research, as well as the National Science Foundation.

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