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Developmental xenocortication using human-derived organoids in mice

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The inaccessibility of human brain tissue limits the study of human development and function, a challenge that human stem-cell-derived neural models are beginning to address1,2. Transplantation of neural organoids into rodent hosts enables the in vivo study of aspects of human neurodevelopment and circuit function, alongside behavioural phenotyping of the host animals. However, spatial limitations and competition with host circuits constrain the integration of neural organoids, which is critical for studying disease. Here we establish a transplantation platform using a genetic strategy to effectively deplete glutamatergic neurons from mouse neocortex and hippocampus (apallial) and neonatally engraft the cortical cavity with human stem-cell-derived cortical organoids (hCO) to generate xenocortical mice. This leads to robust graft growth with hCOs occupying most of the cortical volume and generating a diversity of human cortical cell types, including layer 5 extratelencephalic projection neurons. Human cortical neurons integrate with the mouse nervous system, and in vivo cortical graft-wide calcium imaging and electrophysiological analyses revealed patterns of organized activity resembling developing circuits. Behavioural analyses of apallial and xenocortical mice revealed broadly preserved locomotion alongside selective differences in limb coordination and altered organization of spontaneous behaviour. Lastly, this platform enabled behavioural readouts in a model of injury to developing human cortical cells. We envision that xenocortication will be useful for obtaining circuit- and behaviour-level readouts using human neurons to study neurodevelopment, model disease and develop therapeutics.

Part-human part-mouse brain developed in science breakthrough

Neuroscientists in the US have successfully adapted mice to have functioning human cells inside their own brains.

The researchers hope that potential treatments for psychiatric and neurodevelopmental diseases that only occur in humans could now be tested on the laboratory rodents.

While mice with brains that are partly human might sound like a Kafkaesque experiment, the scientists said these are not "mice that think like humans".

The animals are genetically engineered – and surgically altered – so that some of their brain tissue is human.

The scientists said their work, published in the journal Nature, was carried out with independent ethical scrutiny.

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