In mice with a sharply reduced native cortex, human tissue occupied 91.9% of total cortical volume and integrated into neural pathways

In mice with a sharply reduced native cortex, human tissue occupied 91.9% of total cortical volume and integrated into neural pathways

On September 16, Nature published a study on mice that received four human cortical organoids transplanted several days after birth. Each organoid is a three-dimensional fragment of developing cortex grown from stem cells. Three months later, human tissue accounted for an average of 91.9% of the combined cortical volume across seven measured animals.

In a 2022 study, human organoids had already been transplanted into the cortex of newborn rats: the neurons matured and formed connections with the animals' nervous systems, but the rapidly growing rat cortex took up nearly all available space. In the present experiment, the mice were genetically engineered to have a sharply reduced future neocortex and hippocampus, freeing room for the graft.

The graft survived in 25 of 29 mice and grew roughly 4.7-fold between the second and third months. Tracers placed in nerve fibers showed that the graft receives input from the preserved regions of the mouse brain, while its projections extend to subcortical structures and the cervical spinal cord. Coordinated waves of electrical activity were recorded in the human tissue, and these waves were linked to movements of the mouth and snout.

In the Y-maze, a maze with three arms, mice carrying the graft alternated routes above chance level, whereas control animals with reduced cortex and no graft chose randomly. After five hours in an environment containing 5% oxygen, the human tissue mounted a cellular response to oxygen deprivation, and gait parameters in these mice changed. A single animal in this setup allows researchers to compare an insult to developing human tissue, its cellular response, and a resulting change in behavior.

The organoids used in this study recapitulate the developing human cortex. Transplantation was performed several days after birth, when the principal connections of the mouse brain had already formed. The authors note that more mature tissue, more ordered cortical layers, and earlier transplantation windows would each require separate ethical frameworks.