For the first time, human brain organoids were implanted into the mouse cortex, and they responded to visual stimuli...

A team of engineers and neuroscientists has demonstrated for the first time that human brain organoids implanted in mice have established functional connections to the animal cortex and responded to
external sensory stimuli.
The implanted organoids respond to visual stimuli in the same way as surrounding tissues, and thanks to an innovative experimental setup that combines a transparent graphene microelectrode array and two-photon imaging, the researchers were able to observe this phenomenon in real time over several months
.

The research 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 Dec.
26 issue of Nature Communications.

Human cortical organoids are derived from human induced pluripotent stem cells, which are usually derived from skin cells
.
These brain organoids have recently become promising models
for studying human brain development as well as a range of neurological disorders.

But so far, no research team has been able to demonstrate that human brain organoids implanted in the mouse cortex can have the same functional properties and respond
to stimuli in the same way.
This is because the technology used to record brain function is limited, and it is often impossible to record activity
that lasts only a few milliseconds.

The UC San Diego-led team solved this problem by developing experiments that combined microelectrode arrays made of transparent graphene with two-photon imaging, a microscopy technique that can image
biopsies up to a millimeter thick.

Madison Wilson, lead author of the paper and a doctoral student in the Kuzum research group at the University of California, San Diego, said: "No other study has been able to record
both optically and electronically.
Our experiments show that visual stimulation elicits an electrophysiological response in organoids that matches
the response of the surrounding cortex.
”

The researchers hope that this combination of innovative neural recording technology to study organoids will serve as a unique platform for the comprehensive evaluation of organoids as models of brain development and disease, and to study their use as neuroprosthetics to restore function
in lost, degenerated or damaged brain regions.

Kuzum said: "This experimental setup provides an unprecedented opportunity
to study the dysfunction of human neural network levels behind developmental brain diseases.
"

Kuzum's lab first developed transparent graphene electrodes in 2014 and has been advancing the technology
ever since.
The researchers used platinum nanoparticles to reduce the impedance of the graphene electrode by a factor of 100 while keeping the electrode transparent
.
Low-impedance graphene electrodes enable recording and imaging neuronal activity
at the macroscopic scale and at the single-cell level.

By placing these electrode arrays on the transplanted organoids, the researchers were able to record neural activity
in real time from the implanted organoids and the surrounding host cortex.
Using two-photon imaging, they also observed that the blood vessels of the mice grew into organoids that provided the implants with the necessary nutrients and oxygen
.

The researchers applied visual stimulation — an optical white LED — to mice implanted with organoids while placing the mice under
a two-photon microscope.
They observed electrical activity in the electrode channels above the organoids, indicating that the organoids responded to stimuli in the same
way as surrounding tissues.
Electrical activity travels
through functional connections from the area implanted in the organoid area closest to the visual cortex.

In addition, their low-noise transparent graphene electrode technology was able to electrically record spike activity
in organoids and surrounding mouse cortex.
Graphene recordings show increased power of gamma oscillations, phase locking
of slow-oscillating spikes from organoids to the mouse visual cortex.
The findings suggest that the organoids establish synaptic connections with surrounding cortical tissue three weeks after implantation and receive functional input
from the mouse brain.
The researchers continued these chronic multimodal experiments for 11 weeks and showed the functional and morphological integration
of the implanted human brain organoids with the host mouse cortex.

Next steps include longer experiments involving neurological disease models, and incorporating calcium imaging in an experimental setting to visualize peak activity
in organoid neurons.
Other methods can also be used to trace axon projections
between organoids and the mouse cortex.

"We envision that on the road ahead, the combination of stem cell and neural recording technologies will be used to model diseases under physiological conditions; examine patient-specific organoid candidate treatments; and assessing the potential of organoids to restore specific lost, degenerative, or damaged brain regions," Kuzum said
.