Human Neurons Transplanted into Mouse Brains: 2 Amazing Studies

See, for years, we’ve been poking and prodding at the mysteries of the human brain, trying to figure out how this exquisitely complex three-pound universe cooks up consciousness, creativity, and the crushing realization that you forgot to switch the laundry. We’ve used everything from fMRI scans that look like psychedelic light shows to fruit flies with human genes. But what if we could actually take a tiny piece of human brain, plug it into another living organism, and see what happens? Turns out, some clever folks are doing just that with mice, and the implications are, to put it mildly, significant… and for some reason these studies make me want to re-watch the classic 1982 animated film, “The Secret of NIMH.”

Two Studies That Make You Go “Whoa!”

There are 2 journal articles that I am fully obsessed with, both emanating from Chinese research institutions, and both diving headfirst into this fascinating, slightly Frankensteinian territory.

The first (Dong et al., 2021), published in Molecular Psychiatry, is like a proof-of-concept with a side of anxiety. These researchers weren’t messing around with disease models initially; they wanted to see if human cerebral organoids – think of them as 3D blobs of lab-grown human brain tissue that mimic some aspects of early human brain development – could even survive and connect in a mouse brain. And boy, did they. They optimized a way to grow these small organoids and then they injected these tiny human brain bits into the medial prefrontal cortex of mice. (You can read a previous article about cerebral organoids here)

Now, you might imagine these human cells would just sit there, a foreign entity in a bewildered host. But no. Within a month, these grafted human organoids didn’t just survive; they sent out long, probing projections – some over 4.5 millimeters – reaching deep into the basal brain regions of the mice. That’s like Manhattan reaching out and touching Philadelphia in mouse terms. More than that, these human neurons developed the characteristics of mature, glutamate-releasing brain cells and, crucially, the transplanted human neurons formed two-way synaptic connections with the existing mouse neurons. They weren’t just listening; they were talking back. And the kicker? Mice with these human brain grafts showed an increased freezing response to a fear-inducing sound, suggesting that the human tissue had somehow integrated into the mouse circuitry and altered its behavior. It’s a small change, perhaps, but a stunning demonstration of functional integration.

The second study (Zheng et al., 2023), appearing in Theranostics, takes this a step further, focusing on a disease that gnaws at millions of lives: Parkinson’s. Here, the researchers generated human induced pluripotent stem cell-derived midbrain organoids – specifically designed to contain dopamine-producing neurons, the very cells that wither away in Parkinson’s. They then transplanted these organoids made with human genes into the striatum of transgenic mice that had been engineered to mimic Parkinson’s. (You can read a previous article about transgenic animals here)

The results here are genuinely hopeful, albeit still in the realm of animal models. The human midbrain organoids not only survived in the mouse brains but also matured into dopamine-producing neurons. Twelve weeks post-transplantation, a significant portion of the grafted cells were producing a key enzyme in dopamine synthesis (tyrosine hydroxylase) and expressed markers indicating they were becoming the specific type of dopamine neurons lost in Parkinson’s. Even more compelling, these transplanted organoids led to a reversal of motor function deficits in the Parkinsonian mice, and again, established bidirectional connections with the host brain. Using sophisticated techniques to trace neural circuits, they even identified the host brain regions that were communicating with the human grafts. This study also addressed safety concerns, showing no evidence of tumor formation or overgrowth from the transplanted organoids.

So, what we have here are two different studies, using different types of human organoids and targeting different brain regions in mice, both converging on a remarkable finding: human neural tissue can not only survive transplantation into a rodent brain but can also functionally integrate into the existing neural circuits, leading to measurable behavioral consequences. Am I the only one who finds this unbelievably interesting!!!

Beyond the Lab: What Does This Mean for Our Future?

Now, let’s think about what these studies could mean for us humans (I say COULD!!… because the shift from studies in animal models to actual humans is actually a giant leap).

Understanding Brain Development and Disease: These studies may allow us to dissect some of the intricate processes of human brain development. By observing how these human organoids mature and integrate in a living system, researchers may gleam insights into the cellular and molecular mechanisms that govern neural circuit formation, something incredibly difficult to study directly in human embryos. This knowledge can then be leveraged to better understand neurodevelopmental disorders like microcephaly. Imagine being able to witness, in real-time within a living brain, the subtle missteps that lead to neurodevelopmental diseases.

Similarly, these in vivo models provide platforms for studying other types of neurological diseases, including neurodegenerative diseases. The Parkinson’s study is a prime example, offering a more complex and potentially more relevant model than traditional 2D cell cultures or even purely genetic mouse models. We can now study how human Parkinson’s-affected neurons behave in a living brain environment, how they interact with surrounding cells, and test the efficacy of potential therapies in a more physiologically relevant context. This could significantly accelerate drug discovery and the development of novel treatment strategies.

Regenerative Medicine and Cell Therapy: Of course, the most tantalizing prospect is the one you are already thinking about: regenerative medicine. The success of the Parkinson’s study (Zheng et al., 2023) in restoring motor function in mice offers a glimmer of hope for future cell-based therapies in humans. Imagine being able to generate healthy dopamine neurons from a patient’s own stem cells and transplant them to repair the damaged circuits in their brain. This could potentially offer a more targeted and effective treatment for Parkinson’s, going beyond simply managing symptoms with drugs like levodopa.

Even the first study (Dong et al., 2021), while not directly focused on therapy, also hints at the possibility of repairing other types of brain damage or dysfunction. Could we one day use human cerebral organoid transplants to help rebuild circuits damaged by stroke or traumatic brain injury? Could we potentially augment cognitive function by integrating lab-grown neural tissue? These are big, ethically complex questions, but the foundational research is now being laid(!). The fact that these transplanted neurons can form functional connections and influence behavior suggests that the integration is not just structural but also functional.

Drug Discovery and Personalized Medicine: These in vivo organoid models could revolutionize drug screening. Instead of testing drugs on simple cell cultures or relying solely on animal models that may not perfectly recapitulate human disease, we could test them on human neural tissue integrated into a living system. This could lead to the identification of drugs that are more effective and have fewer side effects in humans. Furthermore, by using organoids derived from a specific patient’s stem cells, we could potentially develop personalized therapies tailored to their unique genetic and disease profile.

The Caveats and the Creep Factor

Now, before we get too carried away with visions of human brain upgrades, let’s pump the brakes and acknowledge the significant challenges and ethical considerations.

Scale and Complexity: Mouse brains are smaller and simpler than our own. While these studies show integration at a basic level, the complexity of human cognition arises from stunningly complex interconnected networks of billions of neurons. Replicating that level of complexity with transplanted organoids in a mouse brain seems like an insurmountable challenge. The organoids themselves, while impressive, only capture certain aspects of human brain development and lack the full cellular diversity and intricate architecture of a mature human brain.

Long-Term Integration and Function: The long-term survival, stability, and functional maturation of these grafts need further investigation. Will these human neurons continue to integrate and behave appropriately over the lifespan of the host animal? Could they potentially form aberrant connections or contribute to unintended consequences? The behavioral changes observed in the first study, while significant, were relatively simple. Understanding the potential impact on more complex cognitive functions requires much more research.

Ethical Minefield: Transplanting human brain tissue into animals inevitably raises ethical concerns. As these grafts become more sophisticated and potentially contribute more significantly to the host’s brain function, questions about the animal’s sentience and welfare become increasingly critical. The possibility of creating animals with enhanced cognitive abilities or altered states of consciousness (again, I have an urge to watch “The Secret of NIMH”), however remote it may currently seem, demands careful consideration and robust ethical frameworks. The creep factor is real, and open, public discussion about the ethical boundaries of this research is essential.

Immunological Rejection and Safety: While the studies used immunodeficient mice to prevent immediate rejection of the human tissue, long-term immunological compatibility and the potential for unforeseen immune responses remain important considerations for future therapeutic applications in humans. The Parkinson’s study’s focus on preventing tumor formation is crucial, as the use of stem cell-derived therapies carries the inherent risk of uncontrolled cell growth.

Final Thoughts

Despite these challenges, the research coming out of these labs represents a significant and fascinating leap forward in our ability to study and potentially manipulate the most complex organ/structure in the known universe (i.e., the human brain). These miniature human brain organoids, finding a home and forging connections within the brains of mice, offer an newly emerging window into the fundamental mechanisms of neural integration and behavior.

While we are still a long way from plugging in brain upgrades (yes please) or curing complex neurological disorders with a simple transplant, these studies provide compelling evidence that cross-species neural integration is possible and can have functional consequences. This knowledge will certainly be valuable as we continue to unravel the mysteries of the human brain, develop new therapies for devastating neurological diseases, and grapple with ethical implications of tinkering with the very essence of what makes us who we are.

P.s. Yes, I realize this is the second article that focuses on cerebral organoid studies… I have no excuse. I am obsessed with this topic.

Reference

Dong, X., Xu, S. B., Chen, X., Tao, M., Tang, X. Y., Fang, K. H., … & Liu, Y. (2021). Human cerebral organoids establish subcortical projections in the mouse brain after transplantation. Molecular Psychiatry, 26(7), 2964-2976. https://doi.org/10.1038/s41380-020-00910-4

Zheng, X., Han, D., Liu, W., Wang, X., Pan, N., Wang, Y., & Chen, Z. (2023). Human iPSC-derived midbrain organoids functionally integrate into striatum circuits and restore motor function in a mouse model of Parkinson’s disease. Theranostics, 13(8), 2673. https://doi.org/10.7150/thno.80271