In a first, human brain organoids placed in the mouse cortex react to visual stimuli
Engineers and neuroscientists at the University of California, San Diego have shown for the first time that mice implanted with human brain organoids have functional connectivity to their cortex and respond to external sensory stimuli.
A novel experimental setup that combines transparent graphene microelectrode arrays and two-photon imaging allowed researchers to make this observation over a period of months in real time. The implanted organoids responded to visual stimuli in the same manner as surrounding tissues, according to the press release.
As stated by researchers, human cortical organoids are made from human induced pluripotent stem cells, which are often made from skin cells. These brain organoids have lately emerged as viable models for studying human brain development as well as a variety of neurological diseases.
No one has been able to exhibit it until now
But no research team had previously been able to show that mouse cortex-implanted human brain organoids could exhibit the same functional characteristics and respond to stimuli in the same way. This is due to the limitations of the recording technology for brain activity, which frequently make it impossible to capture activity lasting only a few milliseconds.
Led by Duygu Kuzum, a faculty member in the University of California San Diego Department of Electrical and Computer Engineering, the team collaborated with Anna Devor’s lab at Boston University, besides Alysson R. Muotri’s lab at UC San Diego; and Fred H. Gage’s lab at the Salk Institute.
“No other study has been able to record optically and electrically at the same time,” said Madison Wilson, the paper’s first author and a Ph.D. student in Kuzum’s research group at UC San Diego. “Our experiments reveal that visual stimuli evoke electrophysiological responses in the organoids, matching the responses from the surrounding cortex.”
In order to study organoids, researchers are combining cutting-edge neural recording techniques, and they believe that this will provide a one-of-a-kind platform for evaluating organoids as models for both brain development and disease as well as looking into their potential application as neural prosthetics to replace lost, degenerated, or damaged brain regions.
“This experimental setup opens up unprecedented opportunities for investigations of human neural network-level dysfunctions underlying developmental brain diseases,” said Kuzum.
Researchers applied a visual stimulus
While using two-photon microscopy on the mice with implanted organoids, researchers gave the mice a visual stimulation using an optical white light LED. The organoids’ electrode channels showed electrical activity, indicating that they were responding to the stimuli in a manner similar to neighboring tissue.
“We envision that, further along the road, this combination of stem cells and neurorecording technologies will be used for modeling disease under physiological conditions; examining candidate treatments on patient-specific organoids; and evaluating organoids’ potential to restore specific lost, degenerated or damaged brain regions,” Kuzum said.
The study was published in Nature Communications on December 26.
Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain.
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