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Corticothalamic assembloids recapitulate human fetal brain morphologies and enhance neuronal complexity

ABSTRACT: Neuronal morphology governs how neurons connect, integrate, and process information, offering critical insights into the functional architecture of the brain. Characterizing the three-dimensional (3D) morphology of individual neurons is key not only for mapping circuit connectivity but also for understanding the cellular diversity that emerges during development. Neural organoids are valuable models of human brain development and disease, yet their morphological complexity remains poorly characterized despite advances in single-cell transcriptomics. Here, we use 3D confocal imaging and manual reconstruction of 735 neurons to analyze forebrain (dorsal and ventral) and thalamic (dorsal and ventral) organoids, as well as forebrain, thalamic, and corticothalamic assembloids. We find that organoids and assembloids exhibit distinct morphologies resembling fetal brain neurons, including immature pyramidal-like, double-bouquet, and bushy-like neurons. Interregional assembloids show greater neuronal morphological complexity than individual organoids, with more extensive dendritic branching, longer projections, and diverse soma shapes. Corticothalamic assembloids further display features of emerging connectivity. Complementary transcriptomic profiling supports regional identity and reveals expression of genes involved in projection guidance. We observe dendritic spines with excitatory and inhibitory profiles and varicosities, indicative of maturing synaptic architecture. Together, our work makes an initial effort in describing the diversity of neuronal morphology in human neural organoids and assembloids. It further establishes structural phenotyping as a critical dimension for validating human neural models and underscores their value for modeling morphofunctional disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325828 | GEO | 2026/08/27

REPOSITORIES: GEO

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Project description:Neural organoids are invaluable model systems for studying neurodevelopment and neurological diseases. For this purpose, reproducible differentiation protocols are needed that minimize inter-organoid variability whilst generating neural organoids that physiologically resemble the brain area of interest. Currently, two main approaches are used: guided, where the differentiation towards neuroectoderm and subsequently specific CNS regions is driven by applying extrinsic signalling molecules, and unguided, where the intrinsic capability of pluripotent stem cells to generate neuroectoderm without external signalling is promoted. Despite the importance for the field, the resulting differences between these models have not been directly investigated. To obtain an unbiased comparison, we performed a multi-omic analysis of forebrain organoids generated using a guided and unguided approach focusing on proteomic, lipidomic and metabolomic differences. Furthermore, we characterised differences in phosphorylation and sialylation states of proteins, two key post-translational modifications (PTMs) in neurodevelopment, and performed single cell transcriptomics (scRNAseq). The multi-omic analysis revealed considerable differences in neuronal-, synaptic and glial content, indicating that guided forebrain organoids contain a larger proportion of neurons, including GABAergic interneurons, and synapses whereas unguided organoids contain significantly more GFAP+ cells and choroid plexus. Furthermore, substantial differences in mitochondrial- and metabolic profiles were identified, pointing to increased levels of oxidative phosphorylation and fatty acid β-oxidation in unguided forebrain organoids and a higher reliance on glycolysis in guided forebrain organoids. Overall, our study comprises a thorough description of the multi-omic differences arising when generating guided and unguided forebrain organoids and provide an important resource for the organoid field studying neurodevelopment and -disease.

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Corticothalamic assembloids recapitulate human fetal brain morphologies and enhance neuronal complexity

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