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Generation of human pineal gland organoids with melatonin production for disease modeling.
The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.
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Electronmicroscopic investigation of rat substantia nigra after chronic amphetamine treatment. II. Changes in the glial cells and blood vessels.
The changes in the glial cells and blood vessels of substantia nigra of albino rats were examined at ultrastrucural level after chronic treatment with amphetamine. The animals were injected daily with 5 mg/kg dl-amphetamine i.p. for 90 days. Astroglial and oligodendroglial cells are richer in cytoplasmic organelles. Much more frequently strocytes appear to be satellites of the nerve cells. Dense lamellar myelin-like bodies may be seen in the cytoplasm of oligodendrocytes. Endothelial cells and pericytes have more pinocytous vesicles, osmiophilic granules and mitochondria. Large dense bodies with homogeneous structure fill the cytoplasm of part of the pericytes. The present article discusses the changes observed.
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Letter: Electron microscopy of the somatic spine in the rabbit hippocampus.
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Air-Liquid interface midbrain organoids model the pathological features of Parkinson's disease.
Human-induced pluripotent stem cell-derived midbrain organoids offer a promising platform for modeling Parkinson's disease (PD). Yet, their utility has been limited by the absence of microglia and the development of a necrotic core during maturation. Here, we present an air-liquid interface (ALI) slice culture system for extended cultivation of midbrain organoids (mORGs), enabling efficient microglial integration, improved neuronal viability, and enhanced functional maturation. Compared with conventional mORGs grown in suspension cultures, the ALI method supports more consistent engraftment of microglial progenitors and the development of astrocytes and oligodendrocyte progenitors, as revealed by single-cell RNA sequencing. Functionally, ALI-mORGs exhibited robust and reproducible neural network activity, with N-methyl-D-aspartate (NMDA) stimulation reliably inducing synchronous bursting, as measured by 3D microelectrode array recordings. Importantly, exposure to alpha-synuclein (αSyn) preformed fibrils triggered the progressive accumulation of phosphorylated αSyn inclusions, closely recapitulating key features of PD pathology. The ALI-mORG model addresses major limitations of existing systems and provides a more physiologically relevant platform for investigating cellular mechanisms of PD and for supporting future therapeutic strategies.
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SMALL BLOOD VESSELS AND THE ORIGIN OF PHAGOCYTES IN THE RAT CEREBRAL CORTEX FOLLOWING HEAVY PARTICLE IRRADIATION.
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Morphological aspects of the functional synchronization of supraoptic nucleus neurons.
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MyeliMAP: a microfluidic-multielectrode array hybrid platform to investigate oligodendrocyte function in human iPSC derived brain-like networks.
Oligodendrocytes are the myelinating glia of the central nervous system (CNS), essential for rapid signal propagation, metabolic support, and neuronal health. While rodent-based cultures and organoid systems have provided insights into oligodendrocyte biology, they fall short of capturing human-specific features of myelination or integrating structural and functional readouts. Here, we present MyeliMAP (Myelination MAPping), a human pluripotent stem cell (hPSC) -derived microphysiological and electrophysiological platform that enables robust modeling of CNS myelination. The system combines inducible hPSC-derived neurons and oligodendrocytes in a custom-engineered microfluidic microstructure designed to mimic the developing brain microenvironment, promoting spatially organized axon-glia interactions and controlled myelin sheath formation. Within six weeks, we demonstrate myelin formation and maturation by immunofluorescence and ultrastructural validation using transmission electron microscopy (TEM), confirming compact multilayered wrapping of human axons. Importantly, the microstructure is directly integrated with a high-density microelectrode array (HD-MEA), enabling real-time, long-term functional assessment of neuronal network activity and myelin-dependent changes in signal conduction. This allowed us to demonstrate that oligodendrocyte-based myelinated neurons display enhanced conduction velocity of action potentials compared to neuron monocultures. Moreover, the presence of oligodendrocytes stabilized the temporal neuronal network activity by reducing variability in firing patterns and enhancing synchrony across the culture. This dual structure-function approach surpasses static end-point analyses by coupling morphological validation with dynamic, quantitative measurements of maturing circuit physiology. MyeliMAP provides a reproducible, human-relevant platform to dissect neuron-glia interactions and accelerate discovery of remyelination-promoting strategies for CNS disease.
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Cerebellar organoids get active.
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Taurine suppresses Aβ aggregation and attenuates Alzheimer's disease pathologies in 5XFAD mice and patient-derived cerebral organoids.
Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaque buildup, tau hyperphosphorylation, neuroinflammation, neuronal loss, and impaired adult hippocampal neurogenesis (AHN). Taurine has shown protective effects in various cellular and animal models of AD, though the molecular mechanisms of free taurine and its effects in patient-derived models remain underexplored. This study evaluates taurine's therapeutic potential using integrated in silico, in vitro, in vivo, and ex vivo approaches. In vitro aggregation assays revealed that taurine (10-100 μM) inhibited Aβ42 fibril formation, with transmission electron microscopy showing looser, amorphous fibrils, particularly at higher doses. Computational simulations further supported that taurine binds stably to Aβ peptide fragments and facilitates the dissociation of Aβ dimers. In HT22 cells, taurine protected against Aβ-induced cytotoxicity. In 5XFAD mice, oral administration of taurine (1000 mg/kg, 4 weeks) significantly reduced Aβ accumulation and hyperphosphorylation of tau at Ser202/Thr205 in the dorsal subiculum. Furthermore, taurine attenuated microgliosis, as evidenced by decreased Iba-1 immunoreactivity, protected against neurodegeneration demonstrated by preserving NeuN-positive neurons, and ameliorated deficit of AHN shown by increasing DCX-positive cells in the subgranular zone of the dentate gyrus. Importantly, in cerebral organoids derived from an AD patient carrying the APOE ε4/ε4 genotype, taurine treatment attenuated Aβ accumulation, decreased tau phosphorylation. These findings highlight taurine's multi-target therapeutic potential targeting amyloid aggregation, tau pathology, neuroinflammation and neurogenesis. Our data support taurine emerges as a promising therapeutic candidate for AD.
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Modeling corticotroph deficiency with pituitary organoids supports the functional role of NFKB2 in human pituitary differentiation.
Deficient Anterior pituitary with common Variable Immune Deficiency (DAVID) syndrome results from NFKB2 heterozygous mutations, causing adrenocorticotropic hormone deficiency (ACTHD) and primary hypogammaglobulinemia. While NFKB signaling plays a crucial role in the immune system, its connection to endocrine symptoms is unclear. We established a human disease model to investigate the role of NFKB2 in pituitary development by creating pituitary organoids from CRISPR/Cas9-edited human induced pluripotent stem cells (hiPSCs). Introducing homozygous TBX19K146R/K146R missense pathogenic variant in hiPSC, an allele found in congenital isolated ACTHD, led to a strong reduction of corticotrophs number in pituitary organoids. Then, we characterized the development of organoids harboring NFKB2D865G/D865G mutations found in DAVID patients. NFKB2D865G/D865G mutation acted at different levels of development with mutant organoids displaying changes in the expression of genes involved on pituitary progenitor generation (HESX1, PITX1, LHX3), hypothalamic secreted factors (BMP4, FGF8, FGF10), epithelial-to-mesenchymal transition, lineage precursors development (TBX19, POU1F1) and corticotrophs terminal differentiation (PCSK1, POMC), and showed drastic reduction in the number of corticotrophs. Our results provide strong evidence for the direct role of NFKB2 mutations in the endocrine phenotype observed in patients leading to a new classification of a NFKB2 variant of previously unknown clinical significance as pathogenic in pituitary development.