Scientists replace mouse cortex with human brain tissue to study neurological disorders

Researchers have devised an innovative technique to study human brain tissue within genetically engineered mice. Published in Nature, the study demonstrates that transplanting human stem-cell-derived brain tissue into the skulls of mice allows the human cells to grow significantly, establish long-distance connections, and react to injuries.

This method provides a novel way to observe how human brain circuits function and respond to diseases in a living organism. The primary motivation behind this research comes from the fact that many neurological and psychiatric conditions develop during early brain development; however, obtaining live human brain tissue is challenging, and animal models fail to accurately replicate human genetics or species-specific biological aspects.

While lab-grown organoids and assembloids have advanced the study of human brain development in vitro, they still lack complete features of a fully developed nervous system, such as a functional blood supply, sensory inputs, and motor outputs. Pașca and his team aimed to create a more comprehensive model by allowing human brain clusters to mature within a living animal.

To facilitate this, they genetically modified mice to lack a neocortex and hippocampus, which are crucial brain regions responsible for higher-level cognitive functions and memory. The resulting apallial mice possess approximately half the normal brain volume but can still move around relatively normally. The researchers then transplanted human cortical organoids into the empty brain cavities of these newborn apallial mice in a procedure called xenocortication.

Over time, the human grafts grew dramatically, occupying nearly 92 percent of the available cortical space in the mouse's brain by the third month. The transplanted human cells developed into a diverse range of mature neural cell types, including a particular class of neurons called layer 5 extratelencephalic projection neurons, which are particularly vulnerable in frontotemporal dementia, a neurodegenerative disorder.

The successful growth of these neurons within the xenocortical mice's human tissue provides an opportunity to study them in a living, behaving organism, potentially shedding light on the underlying mechanisms of the disorder. Furthermore, the researchers observed extensive integration between the human tissue and the mouse host.

Fluorescent tracing techniques revealed human nerve fibers extending deep into the mouse's brain and reaching the cervical spinal cord. Meanwhile, the mouse's lower brain regions sent fibers up into the human graft. To verify the functionality of the human brain tissue, the team utilized advanced imaging and electrical recording techniques.

They detected synchronized bursts of electrical activity spreading across the human graft, resembling the organized brain waves seen in early human development. Importantly, this activity correlated with the mouse's physical movements, indicating that the human tissue was electrically active and participating in the animal's nervous system.

Additionally, the xenocortical mice exhibited unique behavioral patterns, which were intermediate between the completely cortex-less mice and those without any graft, suggesting that the human brain tissue might influence the animals' behavior in some capacity.