Amazing stuff!
"... a group from Stanford University has found a way to advance their usefulness for studying brain development and disease — by instead growing [organoids] inside mice that have had large parts of their own brains genetically removed.
Neuroscientists say these “neuro-chimeric” mice, whose brains are half-human — by volume, not by number of neurons — are an important innovation for a field hampered by longstanding challenges in accessing human brain tissue for research. But such models also raise a host of ethical questions that will get thornier the more advanced they become. ..."
"... researchers succeeded in transplanting self-organizing bits of laboratory-grown human brain tissue called cortical organoids into mice specially bioengineered and bred so that almost all of their cerebral cortex was missing. (The cerebral cortex is the outermost “rind” of the brain, to which much of our higher-level functioning such as cognition, language, attention and decision-making is attributed.)
The resulting vastly enlarged cavity in the mice’s brains proved to be a hospitable environment. The human tissue survived, thrived, grew — and developed working connections to the mice’s brain and beyond to the spinal cord. ...
The new methodology should speed research into the underlying biological causes of schizophrenia, epilepsy, profound autism and cerebral palsy ..."
From the abstract:
"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 address.
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."
Stanford Medicine team creates advanced model for studying brain development, disorders "The ability to study brain disorders that arise before birth has taken a leap forward as Stanford Medicine researchers find a new way to grow human brain tissue outside of the human brain."
Fig. 1: Characterization of the apallial mouse model.
Fig. 2: Transplantation of human cortical organoids into the apallial mouse.
