Tiny Brain Organisms: A New Frontier in Neuroscience
Brain organoids offer a fresh approach to studying human brain development and diseases.
Daniel J Lloyd-Davies Sánchez, Feline W Lindhout, Alexander J Anderson, Laura Pellegrini, Madeline A Lancaster
― 9 min read
Table of Contents
- The Challenge of Studying Human Brain Development
- Enter Stem Cell-Derived Brain Organoids
- How Brain Organoids Are Made
- Comparing Mice and Human Organoids
- Development of Mouse Brain Organoids
- Region-Specific Brain Organoids
- The Importance of Long-Term Cultures
- Understanding Neuronal Maturation
- Functional Neuronal Activity
- The Future of Brain Organoids
- Conclusion
- Original Source
Brain Organoids are tiny, lab-grown structures that mimic the human brain's development and function. They are made from Stem Cells, which are special cells that can turn into any cell type in the body. Scientists use these organoids to study the brain because getting access to human brain tissue for research is as easy as finding a unicorn in your backyard.
Just like how a chef needs the right ingredients and recipe to cook a delicious meal, researchers need specific conditions and methods to create these brain organoids. They can grow organoids that represent different parts of the brain, allowing scientists to see how various brain cells develop over time.
Think of brain organoids as "brain in a dish." They let scientists take a closer look at how our brains grow and function without needing to step into the messy reality of living brains.
The Challenge of Studying Human Brain Development
Studying human brain development is tricky. The human brain is incredibly complex and different from that of other animals. For instance, a mouse brain is a lot smaller and less complicated than a human brain. When researchers try to study the human brain by looking at mouse brains, things can get a little messy.
One of the main challenges is that the techniques used in lab studies, like in vitro (outside a living organism) and in vivo (inside a living organism), often don’t match up perfectly. This can lead to differences in how findings in mice translate to humans.
The quest to understand human brain development also faces other hurdles. For instance, human brain tissue is hard to get, and when researchers do manage to get some, they often can’t experiment with it in the same way they would with mice. There’s a lot to unpack in this complicated web of research, but the good news is that scientists are always looking for new ways to study the brain.
Enter Stem Cell-Derived Brain Organoids
In recent years, scientists have discovered a nifty solution: brain organoids derived from stem cells. These tiny brain structures give researchers a chance to watch human neurodevelopment from the comfort of their lab benches.
Using stem cells, researchers can create mini-brains that develop features similar to those found in real human brains. This has opened up exciting avenues for research, allowing for the study of specific brain conditions like Alzheimer’s disease and microcephaly. Brain organoids provide a more relevant context than mouse models, which can sometimes fail to show the same disease traits seen in humans.
How Brain Organoids Are Made
Creating brain organoids involves a series of carefully timed steps. Scientists start with stem cells and gradually introduce specific growth factors, sort of like adding ingredients to a recipe. The stem cells then start to differentiate and cluster together, forming mini-brain-like structures.
Once these organoids grow, they can be monitored to study their development over time. It’s like watching a puppy grow; you get to see all the little changes that happen day by day.
Researchers can even use technology like gene editing on these organoids, allowing them to create models of diseases. They can compare how organoids from healthy individuals differ from those derived from people with certain conditions, giving them insights into how those diseases work.
Comparing Mice and Human Organoids
Since the mouse is one of the most popular animals for research, it is often used as a reference point for comparing findings from human brain organoids. One might think of it as the Mario Kart of the scientific world: small, fast, and well-known.
Mice and humans have different brain sizes and shapes, which can lead to discrepancies in how brain development progresses in the two species. For example, mouse brain organoids often develop faster than human ones. If you’ve ever had a pet hamster, you might know that hamsters can grow up and do hamster things a whole lot faster than a human baby.
This difference in development speed can lead to challenges when trying to use what researchers learn from mouse organoids to make predictions about human brain function. Scientists must find ways to ensure these organoids are truly mimicking the complex nature of human brain development.
Development of Mouse Brain Organoids
Research has shown that mouse brain organoids can help bridge the gap between mice and humans in neurodevelopmental studies. Scientists have recently been successful in generating mouse cerebral organoids using a protocol similar to the one used to create human organoids.
These mouse organoids exhibit some classic features of brain development, such as the establishment of distinct layers and the presence of specialized cell types. It’s like watching a mini-movie of a brain growing up. Over time, these mouse organoids also show signs of maturity, displaying characteristics similar to those found in real mouse brains.
Researchers have found that mouse organoids develop faster than human organoids. For instance, they achieve a state called neurogenesis sooner, meaning the cells start forming into neurons at a quicker pace.
In essence, scientists are beginning to learn that mouse organoids can teach us a great deal about how the brain matures and the best ways to study diseases without needing to jump through all those hoops associated with traditional animal testing.
Region-Specific Brain Organoids
Just like how a city has different neighborhoods, brain organoids can also be designed to represent specific brain regions. These region-specific organoids allow researchers to study the unique characteristics and functions of different parts of the brain.
For instance, researchers can create organoids that mimic the choroid plexus- a part of the brain responsible for producing cerebrospinal fluid (CSF). CSF is super important because it cushions the brain and helps transport nutrients.
By using specific signals to guide the development of these organoids, researchers can create miniatures of the choroid plexus that closely resemble its functional counterparts in living animals. This means that scientists can study diseases related to CSF production or understand how the blood-CSF barrier functions.
The Importance of Long-Term Cultures
One of the coolest aspects of these organoids is how they can be maintained long term. By slicing organoids and placing them in a special culture setup called an air-liquid interface (ALI), researchers can keep them alive for extended periods.
This method allows them to observe the interaction of different brain cells over time. Think of it as inviting your friends over for a long party- the more time they spend together, the better they get to know each other.
As the organoids mature, they develop more complex structures, including synaptic connections, similar to those found in real brain tissue. This helps scientists understand how brain cells communicate and form networks, providing vital insights into brain function and disease.
Understanding Neuronal Maturation
As we learned earlier, the road to mature neurons is a long one. Neurons undergo many changes as they grow, much like teenagers trying to figure out their style.
In mouse organoids, researchers can track these changes through immunostaining, a technique that highlights different cell types and their characteristics. They can see the development of axons (the long projections of neurons) and dendrites (the branching structures that receive signals from other neurons).
As these structures mature, they establish functional networks that enable communication between different parts of the organoid. This means researchers can study how neurons form connections and function together, which is super important for understanding conditions like autism, epilepsy, and other neurological disorders.
Functional Neuronal Activity
What’s even more impressive is that these mouse organoids can exhibit electrical activity resembling that of real neurons. This means that scientists can actually measure and observe how these neurons are "firing" and communicating with each other.
Using special setups like multielectrode arrays, researchers can capture and analyze the electrical signals generated by the organoids. It’s like putting tiny microphones in the organoid party to see who’s talking to whom and how often.
By studying these electrical activities, researchers can learn a lot about how neurons behave, including their firing patterns and conduction velocities. This information helps them compare organoid activity to that of real brain tissue, providing a clearer understanding of how the brain functions in health and disease.
The Future of Brain Organoids
The research on brain organoids is still ongoing, with scientists working to refine their techniques and create even more sophisticated models. These advancements could lead to breakthroughs in our understanding of various neurological conditions and pave the way for new treatments.
Brain organoids could also play a role in personalized medicine. Researchers may eventually be able to create organoids from a patient’s own cells, allowing them to test different treatments and see which one works best. Imagine being able to find the right medication for your brain without having to guess and check like you're trying on shoes.
Overall, brain organoids offer a promising avenue for research that can bridge the gap between traditional animal studies and human applications. They provide scientists with a unique tool to investigate the mysteries of the brain, programming the next generation of neurological research while reducing reliance on live animals.
Conclusion
In conclusion, brain organoids are transforming the way researchers study the brain. By mimicking human brain development, they allow scientists to gain insights into the inner workings of the brain and its associated diseases.
Through techniques that create region-specific organoids and long-term cultures, researchers can observe brain development like never before. As we unlock the potential of these remarkable mini-brains, the future looks bright for neuroscience, offering new hope for understanding and treating brain-related conditions.
So, next time someone mentions "brain organoids," you can smile knowingly, perhaps imagining tiny brains having a party in a dish, all while learning about the fascinating journey of brain development. Who knew science could be so entertaining?
Title: Mouse brain organoids model in vivo neurodevelopment and function and capture differences to human
Abstract: In the last decade since their emergence, brain organoids have offered an increasingly popular and powerful model for the study of early development and disease in humans. These 3D stem cell-derived models exist in a newer space at the intersection of in vivo and 2D in vitro models. Functional benchmarking has so far remained largely uncharacterised however, leaving the extent to which these models may accurately portray in vivo processes still yet to be fully realised. Here we present a standardised unguided protocol to generate brain organoids from mice, the most commonly-used in vivo mammalian model; and in parallel establish a guided protocol for generating region-specific choroid plexus mouse organoids. Both unguided and guided mouse organoids progress through neurodevelopmental stages with an in vivo-like tempo and recapitulate species-specific characteristics of neural and choroid plexus development, respectively. Neuroepithelial cells generate neural progenitors that give rise to different neural subtypes including deep-layer neurons, upper-layer neurons, and glial cells. We further adapted protocols to prolong mouse cerebral organoid (CO) cultures as slices at the air-liquid interface (ALI), enhancing accessibility for long-term studies and functional investigations. In mature mouse ALI-COs, we observed mature glia, as well as synaptic structures and long-range axon tracts projecting to distant regions, suggesting an establishment and maturation of neural circuitry. Indeed, functional analyses with high-density multi-electrode arrays (HD-MEAs) indicate comparable activity to ex vivo organotypic mouse brain slices. Having established protocols for both region-specific and unpatterned mouse brain organoids, we demonstrate that their neurodevelopmental trajectories, and resultant mature features, closely mimic the in vivo models to which they are benchmarked across multiple biochemical, morphological, and functional read-outs. We propose that mouse brain organoids are a valuable model for functional studies, and provide insight into how closely brain organoids of other species, such as human, may recapitulate their own respective in vivo development.
Authors: Daniel J Lloyd-Davies Sánchez, Feline W Lindhout, Alexander J Anderson, Laura Pellegrini, Madeline A Lancaster
Last Update: Dec 24, 2024
Language: English
Source URL: https://www.biorxiv.org/content/10.1101/2024.12.21.629881
Source PDF: https://www.biorxiv.org/content/10.1101/2024.12.21.629881.full.pdf
Licence: https://creativecommons.org/licenses/by/4.0/
Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.
Thank you to biorxiv for use of its open access interoperability.