Researchers have developed hybrid mice that utilize rat neurons for smelling, demonstrating potential new approaches for studying brain diseases.
At Columbia University, scientists have engineered mice with a combination of rat and mouse brains that enable them to perceive scents as rats do. This development illustrates the brain's ability to assimilate foreign cells and could progress our comprehension of and capacity to address human brain disorders.
If mice ever ponder what it’s like to perceive the world like a rat, some are now capable of experiencing that sensation, particularly regarding the sense of smell.
Scientists at Columbia University, led by Kristin Baldwin, have produced mice with hybrid brains – part mouse, part rat – that detect the aromas of the environment with their rat neurons.
This marks the first instance where an organism has been able to utilize the sensory system of another to accurately detect and respond to the environment, shedding light on the brain's adaptability in integrating external brain cells.
“This research is starting to show us how we can expand the flexibility of a brain so that it can accommodate other kinds of inputs, from human-machine interfaces or transplanted stem cells,” says Baldwin, professor of genetics and development at Columbia University Vagelos College of Physicians and Surgeons.
Mouse hippocampus with rat cells (red) and nuclei of both mouse and rat cells (blue). Credit: M. Khadeesh Imtiaz, Columbia University Irving Medical Center
Pursuing Hybrid Objectives
One of the most significant obstacles in comprehending and addressing human brain diseases is the inability to thoroughly grasp these conditions with current research methods.
“We have excellent models of cells in dishes and 3D cultures known as organoids, and they both have their advantages,” Baldwin says, “But none of them allow you to determine if the cells are really functioning at the highest level.”
Hybrid brains will enable researchers to gain greater insight into how brain cells deteriorate or perish and comprehend the principles of repairing and replacing brain components.
“Presently, researchers are transplanting stem cells and neurons into individuals with Parkinson’s and epilepsy. However, we do not truly comprehend how effective that will be,” she adds. “With hybrid brain models, we can begin to acquire some answers and at a faster pace than through a clinical trial.”
Developing Hybrid Brains
In the past, researchers have generated hybrid brains by implanting neurons or grafting pea-sized brain organoids from one species into either an emerging brain or a fully developed one, whether a mouse or rat.
“These experiments have revealed that we are somewhat restricted in when and how we can add brain cells to an existing brain,” Baldwin says. “If the brain has developed to a certain point, the transplanted cells don’t necessarily interconnect appropriately.”
Instead, Baldwin’s team introduced rat stem cells into mouse blastocysts, an early stage in development that occurs just hours after fertilization, so that the rat and mouse cells could grow together and integrate on their own.
The method, called blastocyst complementation, is like a method used to make mice with human immune systems, which have been effective tools for research. However, until this study, the method had not successfully created hybrid brains of two different species.
"What we're doing is really advanced," Baldwin says.
Rat Neurons Restore Sense of Smell in Mice
In the team’s initial hybrid experiments, they looked at where rat neurons appeared in the mouse brain. Rats mature more slowly and have larger brains, but in the mouse, the rat cells followed the mouse’s instructions, speeding up their development and forming the same connections as their mouse counterparts.
"Rat cells could be observed throughout almost the entire mouse brain, which was quite surprising to us," Baldwin says. "This tells us that there are few obstacles to insertion, indicating that many types of mouse neurons can be replaced by a similar rat neuron."
The researchers then checked if the rat neurons had been integrated into a functional neural circuit, in this case, part of the olfactory system, which is crucial to mice for finding food and avoiding predators. By modifying the mouse embryo to deactivate its own olfactory neurons, the researchers could easily determine if rat neurons had restored the animals’ sense of smell.
"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.
Some mice performed better at finding the cookie than others, however. The researchers found that mice that retained their own, silenced olfactory neurons were less successful at finding hidden cookies than mice whose olfactory neurons were engineered to disappear during development.
"This suggests that adding replacement neurons isn't straightforward," Baldwin says. "If you want a functional replacement, you may need to remove dysfunctional neurons that are just sitting there, which could be the case in some neurodegenerative diseases and also in some neurodevelopmental disorders like autism and schizophrenia."
With the hybrid brain system created by Baldwin’s team, researchers can now use the mice to carefully analyze what happened in the different models, which may eventually help improve the success of human cell transplantation.
Primate Hybrids?
One downside of the new hybrid brain system is that the rat cells were randomly distributed in each different animal, a hurdle in extending these studies to other sensory and neural systems in the brain. Baldwin’s lab is currently trying to find ways to drive the inserted cells to develop into just one cell type, which may allow for more precise experimentation.
If inserted cells can be constrained in their development within hybrid brains, it could also open the door to creating hybrid brains with primate neurons. "This would help us get even closer to understanding human disease," Baldwin says.
Reference: “Functional sensory circuits built from neurons of two species” 25 April 2024, Cell.
DOI: 10.1016/j.cell.2024.03.042
