This shows hippocampal cells.
Mouse hippocampus with rat cells (red) and nuclei of both mouse and rat cells (blue). Credit: M. Khadeesh Imtiaz, Columbia University Irving Medical Center

Hybrid Brains: Mice with Rat Neurons Sense Smells

Summary: Researchers made a groundbreaking advancement by developing mice with hybrid brains containing rat neurons, allowing them to perceive odors like rats. This innovation underscores the brain’s remarkable flexibility to integrate and utilize cells from different species, potentially revolutionizing approaches to human-machine interfaces and cell transplantation therapies.

The hybrid mice demonstrated the capability to locate cookies using their rat-derived sense of smell, illustrating the successful functional integration of the rat neurons. While promising, this research also highlights the complexity of neuron replacement, suggesting the need for targeted strategies to remove dysfunctional neurons for effective therapy in neurodegenerative and neurodevelopmental disorders.

Key Facts:

  1. Hybrid Brain Functionality: Mice with rat neurons effectively used their rat-like olfactory abilities to perform tasks, proving that foreign neurons can fully integrate and function within another species’ brain.
  2. Implications for Human Health: This research could accelerate understanding and treatment of neurological conditions by improving models for cell functionality and integration, potentially aiding in conditions like Parkinson’s and epilepsy.
  3. Future Directions: The success with rat neurons in mice opens possibilities for experimenting with primate neurons, potentially bringing researchers closer to understanding human neurological disorders.

Source: Columbia University

If mice ever wonder what it’s like to experience the world as a rat, some are now able to live that dream, at least when it comes to the sense of smell. 

Researchers led by Columbia University’s Kristin Baldwin have created mice with hybrid brains – part mouse, part rat – that sense the odors of the world with their rat neurons.  

It is the first time that an animal has been able to use the sensory apparatus of another to sense and respond accurately to the world and is one indication of how flexible the brain can be in integrating outside 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. 

Hybrid goals 

One of the biggest challenges in understanding and treating diseases of the human brain is that it is impossible to fully understand these disorders with current research methods.  

“We have beautiful models of cells in dishes and 3D cultures called organoids, and they both have their advantages,” Baldwin says.

“But none of them allows you to determine if the cells are really functioning at the highest level.” 

Hybrid brains will allow researchers to better understand how brain cells get sick or die and better understand the rules of repairing and replacing parts of the brain.  

“Right now, researchers are transplanting stem cells and neurons into people with Parkinson’s and epilepsy. But we do not really understand how well that will work,” she adds.

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

Creating hybrid brains 

Researchers have previously created hybrid brains by injecting neurons or transplanting pea-sized brain organoids from one species into either a developing brain or a fully formed one, either a mouse or rat.   

“These experiments have told us that we are somewhat limited 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 wire together 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 technique, called blastocyst complementation, is similar to a technique used to create mice with human immune systems, which have proven to be powerful research tools. But until this study, the technique had not been successful in creating hybrid brains of two different species. 

“What we’re doing is really cutting edge,” Baldwin says.  

Rat neurons restore sense of smell in mice 

In the team’s first hybrid experiments, they examined where rat neurons appeared in the mouse brain. Rats develop at a slower pace and have bigger brains, but in the mouse, the rat cells followed the mouse’s instructions, accelerating their development and making the same kinds of connections as their mouse counterparts. 

“You could see rat cells throughout almost the entire mouse brain, which was fairly surprising to us,” Baldwin says.

“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.” 

The researchers then looked to see if the rat neurons had been integrated in a functional neural circuit, in this case, part of the olfactory system, which is essential to mice for finding food and avoiding predators.

By engineering the mouse embryo to kill or inactivate 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 did 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 plug and play,” Baldwin says.

“If you want a functional replacement, you may need to empty out 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 dissect 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. 

About this neuroscience research news

Author: Helen Garey
Source: Columbia University
Contact: Helen Garey – Columbia University
Image: The image is credited to M. Khadeesh Imtiaz, Columbia University Irving Medical Center

Original Research: Open access.
Functional sensory circuits built from neurons of two species” by Kristin Baldwin et al. Cell


Functional sensory circuits built from neurons of two species


  • Rat stem cells develop in mouse blastocysts to broadly populate two-species brains
  • Rat neurons develop synchronously and synapse with cognate mouse neurons
  • Genetic models of circuit loss or silencing unveil rescue capacity of exogenous neurons
  • Rat sensory neurons restore the primal behavior of food seeking to anosmic mice


A central question for regenerative neuroscience is whether synthetic neural circuits, such as those built from two species, can function in an intact brain.

Here, we apply blastocyst complementation to selectively build and test interspecies neural circuits.

Despite approximately 10–20 million years of evolution, and prominent species differences in brain size, rat pluripotent stem cells injected into mouse blastocysts develop and persist throughout the mouse brain.

Unexpectedly, the mouse niche reprograms the birth dates of rat neurons in the cortex and hippocampus, supporting rat-mouse synaptic activity.

When mouse olfactory neurons are genetically silenced or killed, rat neurons restore information flow to odor processing circuits. Moreover, they rescue the primal behavior of food seeking, although less well than mouse neurons.

By revealing that a mouse can sense the world using neurons from another species, we establish neural blastocyst complementation as a powerful tool to identify conserved mechanisms of brain development, plasticity, and repair.

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