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| Assembloid [3D fluorescent staining] Axons in the thalamus (pink) extended toward the cortex, while those in the cortex (green) extended toward the thalamus at 14 days post-fusion. Image Credit: Fumitaka Osakada |
The Core Concept: Assembloids are multi-region miniature organs derived from induced pluripotent stem (iPS) cells that successfully reproduce complex human neural circuits in vitro.
Key Distinction/Mechanism: Unlike single organoids, assembloids physically fuse multiple regional organoids—such as cortical and thalamic models—to simulate cross-regional biological interactions. This fusion allows axons to extend and form functional synapses between disparate brain regions, initiating wave-like, synchronous neural networks.
Origin/History: Developed to overcome the profound ethical and technical challenges of studying living human brain tissue, this constructivist approach shifts developmental neural modeling away from traditional rodent models toward human-specific cellular biology.
Major Frameworks/Components:
- Induced pluripotent stem (iPS) cells utilized to generate distinct brain region models.
- Thalamus-cortex interaction networks that drive cortical growth and maturation.
- Cortical excitatory neuron subtypes analyzed for synchronous activity: intratelencephalic (IT), pyramidal tract (PT), and corticothalamic (CT) neurons.
Branch of Science: Neuroscience, Stem Cell Biology, Pharmacology
Future Application: The assembloid system provides an advanced, cell-type-specific in vitro platform for analyzing neural origins and testing novel pharmaceutical therapies.
Why It Matters: Elucidating how the thalamus selectively shapes cortical neural circuits is critical for uncovering the underlying etiologies of neurodevelopmental and psychiatric conditions, such as autism spectrum disorder (ASD), and accelerating the discovery of new treatments.
A Japanese research team has successfully reproduced the human neural circuit in vitro using multi-region miniature organs known as assembloids, which are derived from induced pluripotent stem (iPS) cells. With this circuit, the team demonstrated that the thalamus plays a crucial role in shaping cell type-specific neural circuits in the human cerebral cortex.
Our brain’s cerebral cortex contains various types of neurons, and effective communication among these neurons and other brain regions is crucial for activating functions like perception and cognition.
Patients with neurodevelopmental disorders, such as autism spectrum disorder (ASD), exhibit disruptions in the structure and function of neural circuits in the cerebral cortex. Therefore, understanding the principles of these circuits is essential to uncovering the causes of these disorders and developing new medications.
Previous studies in rodents have demonstrated that the thalamus plays a critical role in shaping neural circuits in the cortex. However, it remains unclear how the interaction between the thalamus and the cortex shapes neural circuit formation in the human cortex.
This uncertainty arises from the ethical and technical challenges involved in collecting brain samples from humans. Organoids are three-dimensional structures that mimic organs and are derived from stem cells. They have gained attention as a novel approach to addressing these kinds of limitations.
However, studying complex biological interactions, such as neural circuit formation, requires more than a single organoid. Assembloids, which are created by combining two or more organoids, allow researchers to effectively replicate parts of the human brain’s neural circuits in vitro.
Professor Fumitaka Osakada, graduate student Masatoshi Nishimura, and their colleagues at the Graduate School of Pharmaceutical Sciences, Nagoya University, established assembloids to reproduce the interaction between the thalamus and the cortex in vitro.
The researchers began by generating cortical and thalamic organoids from human iPS cells. They then physically fused these organoids to create assembloids and studied the thalamus-cortex interactions within them.
Their observations revealed that axons in the thalamus extended toward the cortex, whereas those in the cortex extended toward the thalamus, forming synapses with one another. These findings demonstrated that thalamus-cortex interactions in the assembloid operate similarly to those in the human brain.
They next compared gene expression patterns between the cortical side of the assembloid and a single cortical organoid. They found that the former was more mature than the latter, suggesting that thalamus-cortex interactions promote cortical growth and maturation.
The researchers also examined how these thalamus-cortex interactions contribute to the formation of neural circuits in the cortex of the assembloid. They discovered that neural activity propagates from the thalamus to the cortex in a wave-like pattern, forming a synchronous network within the cortex.
Furthermore, the team measured neural activity levels in three primary subtypes of cortical excitatory neurons: intratelencephalic (IT), pyramidal tract (PT), and corticothalamic (CT). They aimed to identify which types of neurons contribute to synchronous neural activity networks.
The results revealed synchronous activity in PT and CT neurons, both of which project to the thalamus. In contrast, no synchrony was observed in IT neurons. These findings suggest that thalamic inputs selectively promote the formation of cell type-specific synchronized networks, enhancing their functional maturation in the assembloid.
The research team successfully reproduced human neural circuits using assembloids. This achievement provides a system to analyze the origins, structures, and functions of these circuits at the cell-type level.
Osakada concluded, “We have made significant progress in the constructivist approach to understanding the human brain by reproducing it. We believe these findings will help accelerate the discovery of mechanisms underlying neurological and psychiatric disorders, as well as the development of new therapies.”
Reference material: What Is: Assembloids
Funding: This work was supported by the Grants-in-Aid from the Japan Society for the Promotion of Science (F.O.; 20K21476, 21H05168, 22H02771, and 25K02553), PRESTO and CREST from the Japan Science and Technology Agency (F.O.; JPMJPR14F6 and JPMJCR1851), CREST and Brain/MINDS 2.0 from Japan Agency for Medical Research and Development (F.O.; JP23gm1510011 and JP24wm0625110), Hoansha Foundation (F.O.), and SRF Foundation (F.O.).
Published in journal: Proceedings of the National Academy of Sciences
Authors: Masatoshi Nishimura, Shota Adachi, Tomoki Kodera, Akinori Y. Sato, Ryosuke F. Takeuchi, and Fumitaka Osakada
Source/Credit: Nagoya University
Edited by: Scientific Frontline
Reference Number: phar121525_01