Rat Cells Help Mice Smell Through Hybrid Brains

Researchers have created mice whose brains are partially composed of rat cells, enabling the animals to perceive odours using another species' neural machinery.

This marks the first occasion on which an animal has relied on another species' senses to recognise and react to its environment, illustrating the brain's remarkable capacity to incorporate distinct kinds of brain cell.

The US researchers say their results may reveal commonalities in the ways brains form, adapt and repair in different species. They could also potentially guide studies of human-machine interfaces and stem-cell transplantation.

"Right now, researchers are transplanting stem cells and neurons into people with Parkinson's and epilepsy," says geneticist Kristin Baldwin from The Scripps Research Institute in the US.

"With hybrid brain models, we can start to get some answers and at a faster pace than a clinical trial."

Rat cells in mouse hybrid brains

Earlier work had produced hybrid brains by moving neurons or small brain-like structures known as organoids between species, including rat tissue grown in mice. Yet these approaches were limited because the introduced cells did not consistently form proper connections with the host brain.

Baldwin and her colleagues set out to determine whether synthetic neural circuits from two species could operate together inside a living brain.

They used a method known as blastocyst complementation, introducing rat stem cells into mouse embryos soon after fertilisation. This enabled rat and mouse cells to develop and integrate naturally alongside one another. It is the first successful use of this particular process to create hybrid brains from cells originating in two distinct species.

Unexpectedly, the mouse brain environment changed the developmental schedule of rat neurons and enabled synaptic links between rat and mouse neurons. This occurred despite rats and mice having evolved independently for millions of years and differing in brain size.

"You could see rat cells throughout almost the entire mouse brain, which was fairly surprising to us," Baldwin explains. "It tells us that there are few barriers to insertion, suggesting that many kinds of mouse neurons can be replaced by a similar rat neuron."

Rat neurons restore the mice's sense of smell

After mouse neurons responsible for smell were disabled or destroyed, rat neurons assumed their role, allowing the brain to process odours and locate food.

"We hid a cookie in each mouse cage, and we were very surprised to see that they could find it with the rat neurons," Baldwin says.

Intriguingly, inactive and dead neurons that remained in place still seemed to influence the animals' behaviour. Mice with deactivated olfactory neurons found it more difficult to locate hidden biscuits than those whose olfactory neurons had been engineered to disappear entirely during development.

"If you want a functional replacement, you may need to empty out dysfunctional neurons that are just sitting there," Baldwin suggests, "which could be the case in some neurodegenerative diseases and also in some neurodevelopmental disorders like autism and schizophrenia."

Future uses for hybrid brain models

While the findings are encouraging, further studies will be needed to establish the consequences of interspecies neural integration and make use of its potential.

A limitation of the new hybrid brain system is that rat cells are scattered at random, which makes the technique harder to apply to other brain systems.

Baldwin's group is attempting to steer the cells towards becoming a particular cell type, which may make experiments more precise. Should it work, the technique might even create hybrid brains containing primate neurons.

"This would help us get even closer to understanding human disease," Baldwin says.

The research was published in Cell.