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[Histochemistry and ultrastructure of the red nucleus of hens (Gallus domesticus)].
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Topography of the neurons responding to estrogen in the hypothalamic arcuate nucleus of immature female mice.
The neurons in the hypothalamic arcuate nucleus (ARC) of 20-day-old female mice were examined by electron microscopy. The administration of estradiol-17 beta during 20 days from the day of birth resulted in the increase of dense-core vesicles (DCVs) in some neuronal perikarya of the middle region of the ARC (middle ARC), while, in the posterior region of the ARC (posterior ARC), the increase of DCVs was less marked. Topographical studies revealed that the neuronal perikarya containing few DCVs were assembled in the ventromedial area of the middle ARC in both control mice and mice given estrogen. Those containing 5 or more DCVs were found predominantly in the ventromedial area of the middle ARC in mice given estrogen. In the posterior ARC, however, the neuronal perikarya containing DCVs seemed to be scattered. The distribution patterns of the diameter of DCVs were significantly different between control mice and mice given estrogen. The administration of estrogen seem to bring about the enlargement in the size of DCVs. These results indicate that the neurons responding to estrogen are present in the ventromedial area of the middle ARC, and suggest that this area is a significant focus in estrogen feedback mechanisms.
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Charting and probing the activity of ADARs in human development and cell-fate specification.
Adenosine deaminases acting on RNA (ADARs) impact diverse cellular processes and pathological conditions, but their functions in early cell-fate specification remain less understood. To gain insights here, we began by charting time-course RNA editing profiles in human organs from fetal to adult stages. Next, we utilized hPSC differentiation to experimentally probe ADARs, harnessing brain organoids as neural specific, and teratomas as pan-tissue developmental models. We show that time-series teratomas faithfully recapitulate fetal developmental trends, and motivated by this, conducted pan-tissue, single-cell CRISPR-KO screens of ADARs in teratomas. Knocking out ADAR leads to a global decrease in RNA editing across all germ-layers. Intriguingly, knocking out ADAR leads to an enrichment of adipogenic cells, revealing a role for ADAR in human adipogenesis. Collectively, we present a multi-pronged framework charting time-resolved RNA editing profiles and coupled ADAR perturbations in developmental models, thereby shedding light on the role of ADARs in cell-fate specification.
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iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric symptoms in Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.
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Computer analysis of organelle translocation in primary neuronal cultures and continuous cell lines.
Organelle translocation in a number of cell types in tissue culture as seen by high-resolution Zeiss-Nomarski differential interference contrast optics was filmed and analyzed by computer. Principal cell types studied included primary chick spinal cord, chick dorsal root ganglion, ratbrain, and various clones of continuous cell lines. Organelle translocations in all cell types studied exhibited frequent, large changes in velocity during any one translocation. The appearance of particles as seen with Nomarski optics was correlated with their fine structures in one dorsal root ganglion neurite by fixing the cell as it was being filmed and obtaining electron micrographs of the region filmed. This revealed the identity of several organelles as well as the presence of abundant neurotubules but no neurofilaments. Primary cell cultures exhibited more high-velocity organelle movements than continuous cell lines. The net progress of an organelle in a given direction was greater in primary neuronal cells than in fibroblasts or continuous cell lines. These findings are correlated with the literature on organelle translocation and axoplasmic transport.
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Anti-Zika virus RNAi in neural progenitor cells.
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Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.
Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.
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On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis.
In 4 patients with neuronal ceroid-lipofuscinoses (NCL) (3 patients with the junvenile type, 1 patient with the late infantile type), the ultrastructural spectrum of residual bodies in the central and peripheral nervous system presented curvilinear profiles in all cases and regions investigated and many more ultrastructural patterns within and beyond regions commonly accessible to biopsy, probably due to age dependence, local tissue and cellular biochemical factors. Sampling from basal ganglia especially yielded combined curvilinear-fingerpint bodies, from peripheral ganglia additional membranous bodies. Residual bodies in NCL were present in almost every cell type, similar to the distribution of regular lipofuscin. Although the classical subgroups of NCL contain electronmicroscopically well defined residual bodies, permitting distinction of the late infantile type from the juvenile type, the ultrastructural differences are more of a quantitative than of a qualitative nature. However, they are not pathognomonic. N.m.r. spectra of ceroid and lipofuscin support the concept of their biochemical similarity, and argue against the proposition that they contain a single major component.
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An in vitro model of neuronal ensembles.
Advances in 3D neuronal cultures, such as brain spheroids and organoids, are allowing unprecedented in vitro access to some of the molecular, cellular and developmental mechanisms underlying brain diseases. However, their efficacy in recapitulating brain network properties that encode brain function remains limited, thereby precluding development of effective in vitro models of complex brain disorders like schizophrenia. Here, we develop and characterize a Modular Neuronal Network (MoNNet) approach that recapitulates specific features of neuronal ensemble dynamics, segregated local-global network activities and a hierarchical modular organization. We utilized MoNNets for quantitative in vitro modelling of schizophrenia-related network dysfunctions caused by highly penetrant mutations in SETD1A and 22q11.2 risk loci. Furthermore, we demonstrate its utility for drug discovery by performing pharmacological rescue of alterations in neuronal ensembles stability and global network synchrony. MoNNets allow in vitro modelling of brain diseases for investigating the underlying neuronal network mechanisms and systematic drug discovery.
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How do vessels proliferate in the capsule of a chronic subdural hematoma?
An ultrastructural study was performed to define the mechanisms of proliferation of macrocapillaries and capillaries in the capsule of chronic subdural hematoma. Mitotic activities of endothelial cells and vascular sprouts may contribute to the vascular proliferation. Platelets may also play an important role. Endothelial cells of proliferating macrocapillaries were highly attenuated except for the nuclear portion and showed variable electron densities. The adjacent endothelial cells had less intimate cellular junctions than the proliferating capillaries. The proliferating endothelial cell sometimes contacted the opposing endothelial cell across the lumen, separating the latter into two compartments. The pericytes varied remarkably in size, shape, and electron density. Proliferating capillaries had a narrowed vascular lumen and were characterized by cuboidal or thickened endothelial cells with enlarged nuclei, numerous pinocytotic vesicles, and cytoplasmic protrusions into the vascular lumen. They occasionally had intimate cellular junctions with interdigitations and slender pericytes of high electron density. Proliferating vessels occasionally had some clear endothelial cells that contained filamentous material and a few dense bodies. These cells might represent degenerated or swollen endothelial cells. However, they showed no evidence of increased permeability. Postdegranulation platelets were sometimes trapped in the endothelial linings. These data indicate that the most important factor for the development of chronic subdural hematoma exists in the vessels of the capsules, which have a marked proliferation potential and a fragile nature. The possibility of transition from proliferating capillaries to macrocapillaries is discussed.