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The mouse cortex is a canonical model for studying how functional neural networks emerge, yet it remains unclear which topological features arise from intrinsic cellular organization versus external regional cues. Mouse forebrain organoids provide a powerful system to investigate these intrinsic mechanisms. We generated dorsal (DF) and ventral (VF) forebrain organoids from mouse pluripotent stem cells and tracked their development using longitudinal electrophysiology. DF organoids showed progressively stronger network-wide correlations, while VF organoids developed more refined activity patterns, enhanced small-world topology, and increased modular organization. These differences emerged without extrinsic inputs and may be driven by the increased generation of Pvalb interneurons in VF organoids. Our findings demonstrate how variations in cellular composition influence the self-organization of neural circuits, establishing mouse forebrain organoids as a tractable platform to study how neuronal populations shape cortical network architecture.
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http://dx.doi.org/10.1101/2025.05.01.651773 | DOI Listing |
Objective: pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell model system, we aim to investigate the molecular and cellular mechanisms underlying the SCN2A-L1342P-associated pathology.
View Article and Find Full Text PDFCell Rep
August 2025
Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria; Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria. Electronic address:
Human brain organoids are powerful in vitro models for brain development and disease. However, protocol and pluripotent cell line choices influence organoid variability and cell-type representation, complicating their use in biomedical research. Here, we systematically analyze the cellular and transcriptional landscape of brain organoids across multiple cell lines using four protocols aimed at recapitulating dorsal and ventral forebrain, midbrain, and striatum.
View Article and Find Full Text PDFNat Commun
August 2025
Department of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Hyogo, Japan.
Anti-pituitary-specific transcription factor (PIT)-1 hypophysitis is an autoimmune disease characterized by hormone secretion impairment from PIT-1-expressing pituitary cells, accompanied by malignancies with ectopic PIT-1 expression. Cytotoxic T cells (CTL) targeting PIT-1-positive cells have been implicated in disease development, yet direct evidence is lacking. As human leukocyte antigen (HLA)-matching is required for modeling T cell-mediated autoimmune diseases, we employ induced pluripotent stem cells (iPSC) to generate pituitary organoids harboring the patients' HLA haplotype and coculture the organoids with PIT-1-reactive CTLs isolated from the patients' peripheral blood mononuclear cells.
View Article and Find Full Text PDFSci Adv
August 2025
Department of Intelligent Systems Engineering, Indiana University Bloomington, IN 47405, USA.
Increasing evidence strongly links neuroinflammation to Alzheimer's disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation.
View Article and Find Full Text PDFDespite their significance, the genetic and molecular bases of neurodevelopmental disorders remain poorly understood. In this study, using human brain organoids and mouse models, we show that loss of , a gene closely associated with microcephaly, disrupts progenitor identity, prolongs mitosis, and alters regional patterning in the forebrain. knockout leads to a caudal identity shift of neural progenitor cells in the organoids and mouse brains, coinciding with aberrant ERK signaling.
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