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An electron microscopic study of the neurosecretory pars intercerebralis--corpus cardiacum system in larvae of the dragonfly, Aeschna cyanae (Müller) (Odonata: Aeschnidae).
The ultrastructural morphology of the medial neurosecretory cells of the pars intercerebralis region of the brain and that of the corpus cardiacum (C) has been described. The medial neurosecretory cells (MNC) are classified as four distinct cell-types--MNC1, MNC2, MNC3 and MNC4 containing the neurosecretory granules (NSG) about 1900 A, 2100 A, 1600 A and 1750 A in diameter, respectively. The varying amounts of NSG have been seen in the axonal tracts, nervi corporis cardiaci and axon terminals in the CC and aortic wall. Two types of intrinsic neurosecretory cells (INC) can be distinguished in the corpus cardiacum--INC1 and INC2 containing the electron dense granules of 3000 A and 2000 A in diameter, respectively. The subcellular mechanisms associated with synthesis and release of the neurosecretory material are discussed.
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Does Zika Virus Lead to Microcephaly in Organoids?
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Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion.
Focal cortical dysplasia type II (FCDII), a major cause of paediatric drug-resistant focal epilepsy, results from brain somatic variants in mTOR pathway genes, including germline and somatic second-hit loss-of-function variants in the mTOR repressor DEPDC5. Here, we present a proof-of-concept model of DEPDC5 two-hit inactivation mosaicism using patient-derived human cortical organoids (hCOs). Mosaic hCOs displayed increased mTOR activity that was rescued by the mTOR inhibitor rapamycin. Mosaic hCOs also exhibited dysmorphic-like neurons and enhanced neuronal excitability, recapitulating key FCDII pathology hallmarks. Single-cell transcriptomics across three developmental stages revealed aberrant differentiation trajectories leading to premature upper-layer neuron generation, upregulated Notch and Wnt signalling pathways in neural progenitors, and altered expression of synaptic- and epilepsy-associated genes in excitatory neurons. In addition, we identified cell-autonomous alterations in metabolism and translation in mosaic DEPDC5 two-hit hCOs. This study provides novel insights into how DEPDC5 deficiency perturbs human corticogenesis, highlighting that mosaic biallelic inactivation of the gene is necessary for FCDII pathogenesis.
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Spatially-restricted inflammation-induced senescent-like glia in multiple sclerosis and patient-derived organoids.
In multiple sclerosis (MS), chronic compartmentalized inflammation is thought to drive relentless clinical deterioration. Here, we investigate the link between unresolved parenchymal inflammation and cellular senescence in MS progression. Single-cell transcriptomic analysis of human brain tissue reveals an accumulation of senescent-like glial cells in diseased white matter, especially in chronic active lesions, and to a lesser extent in the cortex. Spatial transcriptomics show gradients of senescence-like signatures extending from lesion cores to periplaque regions, alongside rewired cellular networks. Experimental induction of senescence in MS hiPSC-derived neural organoids demonstrates that microglia are especially vulnerable to inflammation-induced senescence, which can be partially rescued by CNS-penetrant anti-inflammatory drugs. At the patient level (n = 466), increased 3T MRI-estimated brain-age is observed, especially in individuals with more than four chronic active lesions. These findings suggest that chronic inflammation might accelerate senescence-like processes, potentially contributing to disease progression, and that its modulation might help limit further propagation.
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Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids.
While random X-chromosome inactivation in female cells of placental mammals silences one allele of the majority of X-chromosomal genes, a considerable fraction is only incompletely and variably inactivated. Human model systems to study the dynamics of incomplete X-inactivation are limited mostly to postmortem tissue, thereby disregarding developmental trajectories. Here, we used clonal human female induced pluripotent stem cells to track allele-specific expression of X-chromosomal genes along neural differentiation. We discovered dynamic reactivation and late-silencing of gene expression from the inactive X-chromosome leading to differentiation-induced locus- and lineage-specific usage of the two X-chromosomal alleles. In brain organoids modeling Opitz BBB/G syndrome, an X-linked neurodevelopmental disorder, reactivation of alleles from the inactive X-chromosome rescued cellular phenotypes and led to intermediate manifestations in female tissue. Taken together, our data demonstrate that alleles on the inactive X-chromosome can serve as a critical reservoir dynamically used during differentiation, thereby enhancing resilience of female neural tissue.
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Lipid inclusions in the telencephalic neuroglia of the developing rat.
The presence of lipid vacuoles is a common fact in neuroglial cells and their precursors in the developing rat brain. Simple lipid vacuoles are present in ependymal cells, subependymal cells, spongioblasts and astrocytes. Polymorphic inclusions are observed in subependymal cells, spongioblasts, astrocytes and oligodendrocytes. Great numbers of dense inclusions are found in "premyelinic" oligodendrocytes, while smaller numbers of simple lipid vacuoles are found in the astrocytes of the telencephalic mantle. These results are discussed and related to the better known changes present in the human developing brain.
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Midbrain organoids for Parkinson's disease (PD) - A powerful tool to understand the disease pathogenesis.
Brain Organiods (BOs) are a promising technique for researching disease progression in the human brain. These organoids, which are produced from human induced pluripotent stem cells (HiPSCs), can construct themselves into structured frameworks. In the context of Parkinson's disease (PD), recent advancements have been made in the development of Midbrain organoids (MBOs) models that consider key pathophysiological mechanisms such as alpha-synuclein (α-Syn), Lewy bodies, dopamine loss, and microglia activation. However, there are limitations to the current use of BOs in disease modelling and drug discovery, such as the lack of vascularization, long-term differentiation, and absence of glial cells. To address these limitations, researchers have proposed the use of spinning bioreactors to improve oxygen and nutrient perfusion. Modelling PD utilising modern experimental in vitro models is a valuable tool for studying disease mechanisms and elucidating previously unknown features of PD. In this paper, we exclusively review the unique methods available for cultivating MBOs using a pumping system that mimics the circulatory system. This mechanism may aid in delivering the required amount of oxygen and nutrients to all areas of the organoids, preventing cell death, and allowing for long-term culture and using co-culturing techniques for developing glial cell in BOs. Furthermore, we emphasise some of the significant discoveries about the BOs and the potential challenges of using BOs will be discussed.
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Modelling the human brainin vitro: biofabrication approaches for neural tissue engineering.
The growing demand for physiologically relevant human brain models has driven the development of advanced three-dimensional (3D) systems that can recapitulate key aspects of neural architecture and function. Traditional two-dimensional cultures and animal models fall short in reproducing the structural complexity, cellular diversity, and species-specific characteristics of the human central nervous system. In this review, we provide a comprehensive overview of state-of-the-art scaffold-free and scaffold-based strategies for generating 3D human brain models, with particular emphasis on those derived from pluripotent stem cells. Scaffold-free systems-such as spheroids, organoids, and assembloids-exploit the intrinsic self-organizing capacity of neural cells to recreate spatially and temporally regulated interactions observed during development. Conversely, scaffold-based models utilize biomaterials, including hydrogels and decellularized matrices, to replicate the physical and biochemical properties of the brain microenvironment, providing enhanced control over tissue architecture and reproducibility. A wide range of fabrication methods is discussed, and for each, we assess key features, strengths, and limitations, with particular attention to scalability, reproducibility, and biological relevance. Overall, this review is intended to serve as a practical and well-structured reference for researchers seeking to select or develop the most appropriatein vitro3D brain model for specific applications in neural development and disease modelling.
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High-throughput scNMT protocol for multiomics profiling of single cells from mouse brain and pancreatic organoids.
Single-cell nucleosome, methylome, and transcriptome (scNMT) sequencing is a recently developed method that allows multiomics profiling of single cells. In this scNMT protocol, we describe profiling of cells from mouse brain and pancreatic organoids, using liquid handling platforms to increase throughput from 96-well to 384-well plate format. Our approach miniaturizes reaction volumes and incorporates the latest Smart-seq3 protocol to obtain higher numbers of detected genes and genomic DNA (gDNA) CpGs per cell. We outline normalization steps to optimally distribute per-cell sequencing depth. For complete details on the use and execution of this protocol, please refer to Clark (2019), Clark et al. (2018), and Clark et al., 2018, Hagemann-Jensen et al., 2020a, Hagemann-Jensen et al., 2020b.
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A human striatal-midbrain assembloid model of alpha-synuclein propagation.
Animal models of the pathology of Parkinson's disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cell (hPSC)-derived neural organoids have provided improved access to study PD aetiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modelling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways. Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present, and the neurons, such as dopaminergic neurons and GABAergic neurons, were electrophysiologically active in the hSMAs. Development of hSMAs in the presence of increased α-syn from SNCA overexpression induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to dopaminergic neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to the pathological form in human patients, accumulated in the midbrain area of hSMAs. Treatment with a protein aggregation inhibitor (Anle138b) and an autophagy inducer (rapamycin) reduced α-syn aggregation, indicating the potential of hSMAs for drug testing. This study established hSMAs as a novel platform for modelling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.