2025/12/29 Review Club (Li)
From Organoids to Functional Neural Networks: What Limits Reliability, and How Can We Engineer Toward Intelligence?
Brain organoids reproduce key features of human neural development, yet generating stable and reproducible functional networks remains challenging. This review examines the gap between spontaneous electrical activity and organized network function, focusing on neuronal maturation, batch variability, and synaptic organization. Topics include vascularization and perfusion, the assembly of region-specific organoids into interconnected circuits, and advanced electrophysiological recording technologies. These developments are considered alongside closed-loop stimulation and feedback approaches for investigating learning-like adaptation.
The presentation concludes with an integrated framework linking maturation, circuit assembly, synaptic organization, and functional assessment, highlighting synapse-organizing molecules such as CPTX as potential tools for engineering more reliable and controllable organoid networks.
Reference:
- Faravelli I, Antón-Bolaños N, Brown JR, Arlotta P. Brain organoids: tools for understanding the uniqueness and individual variability of the human brain. Annu Rev Genomics Hum Genet. 2025;26:299–320. DOI: 10.1146/annurev-genom-111522-014009. PubMed
- Sandoval SO, Cappuccio G, Kruth K, Osenberg S, Khalil SM, Méndez-Albelo NM, et al. Rigor and reproducibility in human brain organoid research: where we are and where we need to go. Stem Cell Reports. 2024;19:796–816. DOI: 10.1016/j.stemcr.2024.04.008. PMC
- Kosik KS. Why brain organoids are not conscious yet. Patterns (N Y). 2024;5:101011. DOI: 10.1016/j.patter.2024.101011. PMC
- Urrestizala-Arenaza N, Cerchio S, Cavaliere F, Magliaro C. Limitations of human brain organoids to study neurodegenerative diseases: a manual to survive. Front Cell Neurosci. 2024;18:1419526. DOI: 10.3389/fncel.2024.1419526. PMC
- Yao Q, Cheng S, Pan Q, Yu J, Cao G, Li L, et al. Organoids: development and applications in disease models, drug discovery, precision medicine, and regenerative medicine. MedComm. 2024;5:e735. DOI: 10.1002/mco2.735. pubmed.ncbi.nlm.nih.gov
- Kim JI, Imaizumi K, Jurjuț O, Kelley KW, Wang D, Thete MV, et al. Human assembloid model of the ascending neural sensory pathway. Nature. 2025;642:143–153. DOI: 10.1038/s41586-025-08808-3. Nature
- Sharf T, van der Molen T, Glasauer SMK, Guzman E, Buccino AP, Luna G, et al. Functional neuronal circuitry and oscillatory dynamics in human brain organoids. Nat Commun. 2022;13:4403. DOI: 10.1038/s41467-022-32115-4. Nature Communications
- Fleck JS, Jansen SMJ, Wollny D, Zenk F, Seimiya M, Jain A, et al. Inferring and perturbing cell fate regulomes in human brain organoids. Nature. 2023;621:365–372. DOI: 10.1038/s41586-022-05279-8. PubMed
- Adams JW, Cugola FR, Muotri AR. Brain organoids as tools for modeling human neurodevelopmental disorders. Physiology (Bethesda). 2019;34:365–375. DOI: 10.1152/physiol.00005.2019. PMC
- Zhou JQ, Zeng LH, Li CT, He DH, Zhao HD, Xu YN, et al. Brain organoids are new tool for drug screening of neurological diseases. Neural Regen Res. 2023;18:1884–1889. DOI: 10.4103/1673-5374.367983. PMC
- Anderson WA, Bosak A, Hogberg HT, Hartung T, Moore MJ. Advances in 3D neuronal microphysiological systems: towards a functional nervous system on a chip. In Vitro Cell Dev Biol Anim. 2021;57:191–206. DOI: 10.1007/s11626-020-00532-8. PubMed
- Mancinelli S, Bariselli S, Lodato S. The emergence of electrical activity in human brain organoids. Stem Cell Reports. 2025;20:102632. DOI: 10.1016/j.stemcr.2025.102632. PubMed
- Del Dosso A, Urenda JP, Nguyen T, Quadrato G. Upgrading the physiological relevance of human brain organoids. Neuron. 2020;107:1014–1028. DOI: 10.1016/j.neuron.2020.08.029. PubMed
- Rizzuti M, Melzi V, Brambilla L, Quetti L, Sali L, Ottoboni L, et al. Shaping the neurovascular unit exploiting human brain organoids. Mol Neurobiol. 2024;61:6642–6657. DOI: 10.1007/s12035-024-03998-9. pubmed.ncbi.nlm.nih.gov
- Li XH, Hu N, Chang ZH, Shi JX, Fan X, Chen MM, et al. Brain organoid maturation and implantation integration based on electrical signals input. J Adv Res. 2025;73:375–395. DOI: 10.1016/j.jare.2024.08.035. PubMed
- Trujillo CA, Gao R, Negraes PD, Gu J, Buchanan J, Preissl S, et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell. 2019;25:558–569.e7. DOI: 10.1016/j.stem.2019.08.002. PubMed
- Qian X, Song H, Ming GL. Brain organoids: advances, applications and challenges. Development. 2019;146:dev166074. DOI: 10.1242/dev.166074. pubmed.ncbi.nlm.nih.gov
- Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–379. DOI: 10.1038/nature12517. PMC
- Sawada T, Chater TE, Sasagawa Y, Yoshimura M, Fujimori-Tonou N, Tanaka K, et al. Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids. Mol Psychiatry. 2020;25:2695–2711. DOI: 10.1038/s41380-020-0844-z. PubMed
- Porciúncula LO, Goto-Silva L, Ledur PF, Rehen SK. The age of brain organoids: tailoring cell identity and functionality for normal brain development and disease modeling. Front Neurosci. 2021;15:674563. DOI: 10.3389/fnins.2021.674563. PubMed
- Jiang X, Shen S, Cadwell CR, Berens P, Sinz F, Ecker AS, et al. Principles of connectivity among morphologically defined cell types in adult neocortex. Science. 2015;350:aac9462. DOI: 10.1126/science.aac9462. PubMed
- Mencattini A, Daprati E, Della-Morte D, Guadagni F, Sangiuolo F, Martinelli E. Assembloid learning: opportunities and challenges for personalized approaches to brain functioning in health and disease. Front Artif Intell. 2024;7:1385871. DOI: 10.3389/frai.2024.1385871. pubmed.ncbi.nlm.nih.gov
- Alam El Din DM, Shin J, Lysinger A, Roos MJ, Johnson EC, Shafer TJ, et al. Organoid intelligence for developmental neurotoxicity testing. Front Cell Neurosci. 2024;18:1480845. DOI: 10.3389/fncel.2024.1480845. frontiersin.org
- Jin Y, Guo Y, Li Q, Wu L, Ge Y, Zhao J. Non-invasive and long-term electrophysiological monitoring sensors for cerebral organoids differentiation. Biosensors (Basel). 2025;15:173. DOI: 10.3390/bios15030173.
11/04/2026 11:28 AM | Journal Club