Nature studies the way the brain is connected and functioned

Scientists have developed a research method that allows for a more detailed examination
of brain processes associated with some neurological and psychiatric disorders.
This is achieved by culturing human cortical organoids in culture and inserting them into developing rodent brains to see how they integrate and function over time
.
The study was funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, and published in
the journal Nature.

"This work provides significant advances
in scientists' ability to study the cellular and circuit underpinnings of complex human brain diseases.
" It allows organoids to 'connect' in more biologically relevant environments and function in ways they can't do in a petri dish," said
David Panchision, Ph.
D.
, director of the developmental and genomic neuroscience research branch in NIMH's Division of Neuroscience and Basic Behavioral Sciences.

Sergiu Pasca, MD, Ph.
D.
, from Stanford University in California, and colleagues demonstrated that cortical organoids cultured from human stem cells could be transplanted into the brains of developing rats and integrated with them to study certain developmental and functional processes
.
The findings suggest that transplanted organoids may provide a powerful tool
for studying processes associated with disease development.

Researchers sometimes use cortical organoids — three-dimensional cultures of human stem cells that reflect some of the developmental processes in the typical brain — as models for studying the development and function of certain aspects of the human brain
.
However, cortical organoids lack the connectivity of the typical human brain, limiting their role in
understanding complex brain processes.
Researchers have been trying to overcome these limitations
by transplanting individual human neurons into the brains of adult rodents.
Although these transplanted neurons were connected to rodent brain cells, they did not fully fuse together
due to developmental limitations in the adult rat brains.

In this study, the research team advanced the use of
brain organoids by transplanting an intact human cortical organoid into the developing rat brain.
This technology creates a unit
of human tissue that can be examined and manipulated.
The researchers used methods pioneered by Pașca's lab to create cortical organoids
using human-induced pluripotent stem cells — cells extracted from adult skin cells that have been reprogrammed into an immature stem-cell-like state.
They then implanted these organoids into the rats' primary somatosensory cortex, the part
of the brain involved in processing sensations.

In the rats that received organ transplants, the researchers did not detect any abnormal movement or memory or brain
activity.
Blood vessels from the rat brain successfully supported the implanted tissue and grew
over time.

To understand to what extent organoids can be integrated into the rats' somatosensory cortex, the researchers infected cortical organoids with a viral tracer that travels
through brain cells as an indicator of functional connectivity.
After transplanting the labeled organoids into the primary somatosensory cortex of rats, the researchers detected viral tracers
in multiple areas of the brain, such as the abdominal nucleus and somatosensory cortex.
In addition, the researchers observed a new link
between the thalamus and the transplanted area.
By electrically stimulating and stimulating the rat's whiskers, these connections are activated, indicating that they are receiving meaningful sensory input
.
In addition, the researchers were able to activate human neurons in transplanted organs to modulate reward-seeking behavior
in rats.
The findings suggest that transplanted organoid functions are integrated into specific brain pathways
.

After 7 to 8 months of growth, transplanted brain organoids are structurally and functionally more similar to neurons
in human brain tissue than human brain organoids maintained in cell culture.
The fact that transplanted organoids reflect the structural and functional characteristics of human cortical neurons makes researchers wonder if they can use transplanted organoids to examine various aspects of
the human disease process.

Dr Pașca said: "The promise of this platform lies not only in determining what molecular processes lead to the high maturation of human neurons in living circuits and using it to improve traditional in vitro models, but also in providing behavioral readings
for human neurons.
"

To verify this, the researchers generated cortical organoids with cells from three participants with rare genetic disorders (associated with autism and epilepsy) and three participants without any known diseases, and implanted them into the brains
of rats.
Both types of organoids were integrated into the somatosensory cortex of rats, but organoids from patients with timothy syndrome showed structural differences
.
Organoids generated from cells from patients with Timothy's syndrome did not show these structural differences
in cell culture.

"These experiments show that this new method can capture processes that cannot be detected by existing in vitro models," says
Dr.
Pașca.
"This is important because many of the changes that lead to mental illness are likely to be subtle differences
at the level of neural circuits.
"

Omer Revah, Felicity Gore, Kevin W.
Kelley, Jimena Andersen, Noriaki Sakai, Xiaoyu Chen, Min-Yin Li, Fikri Birey, Xiao Yang, Nay L.
Saw, Samuel W.
Baker, Neal D.
Amin, Shravanti Kulkarni, Rachana Mudipalli, Bianxiao Cui, Seiji Nishino, Gerald A.
Grant, Juliet K.
Knowles, Mehrdad Shamloo, John R.
Huguenard, Karl Deisseroth, Sergiu P.
Pașca.
Maturation and circuit integration of transplanted human cortical organoids.
Nature, 2022; 610 (7931): 319