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Unlocking the epigenome: Single-cell histone profiling in cortical development.
Ditzer et al. used single-cell cytometry by time-of-flight-based method for epigenetic analysis to profile histone modifications in the primary human cortex and cortical organoids, revealing how chromatin states, particularly H3K27me3, govern neural progenitor fate. This study highlights the potential of multiplexed epigenomics in understanding human brain development.
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[Investigations of the fine morphology and distribution of iron deposits in central nervous tissue in experimentally produced marginal siderosis].
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Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus.
Hippocampal interneurons inhibit pyramidal neurons through the release of the neurotransmitter GABA. Given the importance of this inhibition for the proper functioning of the hippocampus, the development of inhibitory synapses must be tightly regulated. In this study, the possibility that neuronal activity and neurotrophins regulate the density of GABAergic inhibitory synapses was investigated in organotypic slice cultures taken from postnatal day 7 rats. In hippocampal slices cultured for 13 d in the presence of the GABA(A) receptor antagonist bicuculline, the density of glutamic acid decarboxylase (GAD) 65-immunoreactive terminals was increased in the CA1 area when compared with control slices. Treatment with the glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione decreased the density of GAD65-immunoreactive terminals in the stratum oriens of CA1. These treatments had parallel effects on the density of GABA-immunoreactive processes. Electron microscopic analysis after postembedding immunogold labeling with antibodies against GABA indicated that bicuculline treatment increased the density of inhibitory but not excitatory synapses. Application of exogenous BDNF partly mimicked the stimulatory effect of bicuculline on GAD65-immunoreactive terminals. Finally, antibodies against BDNF, but not antibodies against nerve growth factor, decrease the density of GAD65-immunoreactive terminals in bicuculline-treated slices. Thus, neuronal activity regulates the density of inhibitory synapses made by postnatal hippocampal interneurons, and BDNF could mediate part of this regulation. This regulation of the density of inhibitory synapses could represent a feedback mechanism aimed at maintaining an appropriate level of activity in the developing hippocampal networks.
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Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome-associated schizophrenia.
Children and adults with 22q11.2 deletion syndrome (22q11.2DS) experience cognitive and emotional challenges and face a markedly increased risk for schizophrenia (SCZ), yet how this deletion alters early human brain development remains unclear. Using cerebral cortex organoids derived from individuals with 22q11.2DS and SCZ, we identify cell-type-specific developmental abnormalities. Single-cell RNA sequencing and experimental validation reveal delayed cortical neuron maturation, with increased neural progenitor proliferation and a reduced proportion of more mature neurons. We observe disrupted molecular programs linked to neuronal maturation, sparser neurites, and blunted glutamate-induced Ca²⁺ responses. The aberrant transcriptional profile is enriched for neuropsychiatric risk genes. MicroRNA profiling suggests that DGCR8 haploinsufficiency contributes to these effects via dysregulation of genes that control the pace of maturation. Protein-protein interaction network analysis highlights complementary roles for additional deleted genes. Our study reveals consistent developmental and molecular defects caused by 22q11.2 deletions, offering insights into disease mechanisms and therapeutic strategies.
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Human neural stem cells dispersed in artificial ECM form cerebral organoids when grafted in vivo.
Human neural stem cells (hNSC) derived from induced pluripotent stem cells can be differentiated into neurons that could be used for transplantation to repair brain injury. In this study we dispersed such hNSC in a three-dimensional artificial extracellular matrix (aECM) and compared their differentiation in vitro and following grafting into the sensorimotor cortex (SMC) of postnatal day (P)14 rat pups lesioned by localised injection of endothelin-1 at P12. After 10-43 days of in vitro differentiation, a few cells remained as PAX6+ neuroprogenitors but many more resembled post-mitotic neurons expressing doublecortin, β-tubulin and MAP2. These cells remained dispersed throughout the ECM, but with extended long processes for over 50 μm. In vivo, by 1 month post grafting, cells expressing human specific markers instead organised into cerebral organoids: columns of tightly packed PAX6 co-expressing progenitor cells arranged around small tubular lumen in rosettes, with a looser network of cells with processes around the outside co-expressing markers of immature neurons including doublecortin, and CTIP2 characteristic of corticofugal neurons. Host cells also invaded the graft including microglia, astrocytes and endothelial cells forming blood vessels. By 10 weeks post-grafting, the organoids had disappeared and the aECM had started to break down with fewer transplanted cells remaining. In vitro, cerebral organoids form in rotating incubators that force oxygen and nutrients to the centre of the structures. We have shown that cerebral organoids can form in vivo; intrinsic factors may direct their organisation including infiltration by host blood vessels.
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The ultrastructure of process formation following treatment with db-cAMP of a Chinese hamster ovary x Chinese hamster brain cell hybrid.
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[Ultrastructural aspects of acute cerebral ischemia during nootropil administration (experimental study)].
Electron microscopy of the sensomotor cortex in 27 rats was performed at varying times (1, 3, 7 days) after arteria carotis communis occlusion. Three groups of rats (5 rats in every group) were treated by nootropil (500 mg/kg daily) in accordance with three time intervals. Control rats were undrugged. More preserved were neurons in the brain of rats treated by nootropil. Neuronal organelles had rare signs of irreversible damages. Membranes were more often preserved, organelles fragmentation and vacuolization were less pronounced. The experimental rats showed neurons containing numerous ribosomes and small new-formed mitochondria. The difference in neuronal structure in treated and untreated rats became more distinct 3-7 days after occlusion. The results obtained are suggested to be connected with the drug ability to normalize ATP metabolism, to stimulate phospholipid synthesis and ribosome function and to increase glucose utilization. The problem of using GABA derivatives in conditions of the most acute brain ischemia is discussed.
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Pineal gland organoids illuminate human melatonin and circadian regulation.
Human pineal development and neuroendocrine regulation remain incompletely understood at the molecular and functional levels. Kiral et al.1 establish human pineal gland organoids (hPGOs) that recapitulate pinealocyte maturation, noradrenergic responsiveness, and melatonin synthesis, providing a platform for investigating circadian dysfunction and disease-associated sleep disturbances.
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Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids.
Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-β (Aβ). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aβ. Furthermore, in mhCOs, we observed reduced expression of Aβ-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer's disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aβ using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.
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Neural Organoids and the Quest to Understand and Treat Psychiatric Disease.