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The mast cells of the mammalian central nervous system. V. The effect of compound 48/80 on the neurolipomastocytoid cells and related areas of the CNS: early changes.
The response of the neurolipomastocytoid cells (NLMs) and elements in their vicinity within the central nervous system of various animal species was studied following injection of the animals with the specific mast cell (MC)-discharger compound 48/80. The observed alterations were grouped into those occurring early (0--21 days) and later (up to 18 months). In the present report, only the acute changes are described, light and electron microscopically. Most experimental animals developed prostration, scratching, acral-type reaction, signs of respiratory distress and salivation, and, in the monkey, uncontrollable somnolence. Within about 2 weeks after the injection some animals (especially guinea pigs) manifested various degrees of limb paralysis. The NLMs, like MCs outside the CNS, responded to injection by various degrees of degranulation, vacuolation, marked variation in granule size, apparent cell loss and sometimes an increase in number. Electron microscopically, particulate breakdown products of the granules of the NLMs appeared in the cytoplasm; occasionally there was suggestive evidence that they had passed inward across the vessel wall to reach the lumen, and also outward through the outermost basal lamina. Perivascular astrocytic feet showed swelling and vacuolation shortly after the injection, which was followed by evidence of gliosis and later scarring; occasionally, alterations in the mitochondria were observed. In the spinal cord of the guinea pig, capillary neoformation was observed with endothelial cells and adjacent NLMs taking up tritiated thymidine. The discussion centers on the partial similarity of response to compound 48/80 of the NLMs to that of MCs outside the CNS, and the probable involvement of NLM-damage in the parenchymal changes.
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Generation of Functional Human 3D Cortico-Motor Assembloids.
Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids. Using rabies tracing, calcium imaging, and patch-clamp recordings, we show that corticofugal neurons project and connect with spinal spheroids, while spinal-derived motor neurons connect with muscle. Glutamate uncaging or optogenetic stimulation of cortical spheroids triggers robust contraction of 3D muscle, and assembloids are morphologically and functionally intact for up to 10 weeks post-fusion. Together, this system highlights the remarkable self-assembly capacity of 3D cultures to form functional circuits that could be used to understand development and disease.
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Human assembloid model of the ascending neural sensory pathway.
Somatosensory pathways convey crucial information about pain, touch, itch and body part movement from peripheral organs to the central nervous system1,2. Despite substantial needs to understand how these pathways assemble and to develop pain therapeutics, clinical translation remains challenging. This is probably related to species-specific features and the lack of in vitro models of the polysynaptic pathway. Here we established a human ascending somatosensory assembloid (hASA), a four-part assembloid generated from human pluripotent stem cells that integrates somatosensory, spinal, thalamic and cortical organoids to model the spinothalamic pathway. Transcriptomic profiling confirmed the presence of key cell types of this circuit. Rabies tracing and calcium imaging showed that sensory neurons connect to dorsal spinal cord neurons, which further connect to thalamic neurons. Following noxious chemical stimulation, calcium imaging of hASA demonstrated a coordinated response. In addition, extracellular recordings and imaging revealed synchronized activity across the assembloid. Notably, loss of the sodium channel NaV1.7, which causes pain insensitivity, disrupted synchrony across hASA. By contrast, a gain-of-function SCN9A variant associated with extreme pain disorder induced hypersynchrony. These experiments demonstrated the ability to functionally assemble the essential components of the human sensory pathway, which could accelerate our understanding of sensory circuits and facilitate therapeutic development.
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"Epileptic" brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology.
Sustained electrical stimulation of the perforant path evokes granule cell population spikes and epileptiform discharges, abolishes recurrent inhibition in the granule cell layer and induces a reproducible pattern of hippocampal damage (see preceding paper, this volume, for electrophysiological and light microscopic findings). Electron microscopic findings described here reveal that the hippocampal damage is identical in pattern and cytopathological detail to that associated with sustained limbic seizures induced by chemical convulsants such as kainic acid, folic acid and dipiperidinoethane. Acutely swollen dendritic segments distributed in a laminar pattern corresponding closely with the termination of putative glutamate or aspartate-containing fibers, including those of the perforant path, were a conspicuous finding. Cell bodies of CA1 and CA3 pyramidal neurons and various interneurons in the hilus and elsewhere displayed degenerative changes ranging from mild to severe. Both the dendritic and somal degenerative changes closely resemble the "excitotoxic" type of damage that the putative transmitters glutamate and aspartate are known to cause. It is proposed, therefore, that sustained electrical stimulation of the perforant path results in excessive synaptic release and accumulation of glutamate (or aspartate) at numerous dendrosomal receptors in the hippocampus with consequent degeneration of the dendrosomal structures housing these receptors. Early excitotoxic effects on interneurons that mediate recurrent inhibition may play an important role in the observed loss of recurrent inhibition and in the evolution of subsequent excitotoxic degeneration in the hippocampus.
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Development of a Human 3D Immune-Competent Neurovascular Model Enabling Time-Resolved Monitoring of Neuroinflammatory Dynamics and Neuroimmune Interactions.
Neuroinflammation disrupts the blood-brain barrier (BBB) and drives neurological disease, but current in vitro MPS and animal models fail to capture its dynamic, human-specific immune complexity. Here, we introduce a 3D human immune-competent BBB (3D-HIC-BBB) platform that reconstitutes the neurovascular unit (NVU) by integrating primary human brain microvascular endothelial cells, astrocytes, brain vascular pericytes, human microglia, and dopaminergic neurospheroids with embedded transepithelial electrical resistance (TEER) microsensors for continuous functional monitoring. Our platform design enables high-resolution of inflammatory NVU dynamics that are inaccessible to conventional endpoint assays. Using controlled exposure to tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS), two distinct triggers of immune responses, we observed stimulus-specific neuroinflammatory responses with distinct temporal and functional signatures with the resistance full width at half maximum (FWHM) for LPS = 15.8 h and TNF-α = 4.3 h. TNF-α exposure elicited a lesser (Δ345 Ω·cm2) but faster drop in resistance and largely faster and reversible recovery than LPS, consistent with transient cytokine-driven disruption. In contrast, LPS induced a delayed yet more severe (Δ560 Ω·cm2) loss. The 3D-HIC-BBB platform distinguishes endotoxin- from cytokine-driven NVU dysfunction and reveals differences in cytokine profiles. It provides a biologically relevant, predictive model for studying neuroinflammation and evaluating anti-inflammatory therapies.
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Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cortical organoids.
Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MECP2 mutations-a missense mutation (R306C) and a truncating mutation (V247X)-using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling >/>DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutations. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABAA receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.
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Actin in the nervous system.
Since synaptic plasticity is an important property of the brain, it is timely to try to understand the possible mechanisms underlying this phenomenon. The role of the cytoplasm for neuronal functions has until now been largely overlooked, the main emphases being on the plasma membrane for fast electrical events and on cytoplasmic organelles for the slower metabolic processes. However, recent studies on the cytoplasm of non-muscle cells have stressed the importance of contractile proteins, like actin, on maintaining the cell shape and a number of vital cellular functions, which may be related to the phase transitions in the cytoplasm. The necessary versatility is conferred on the actin networks by actin-associated proteins and by the free cytosolic calcium. In the nervous system, in addition to actin and myosin, a number of actin regulatory proteins was recently isolated, and they were shown to have properties similar to those of other non-muscle cells. Consequently, actin networks in neurons like those in non-muscle cells may be capable of contraction and phase transitions. The phase transitions have a rapid onset, and they may be quickly terminated or they may last over extended periods of time. In this way actin networks may gain control over the state of the cytoplasm and hence over the function of the neuron. Actin may be, therefore, uniquely suited to regulate various plastic reactions. The cytoplasm of growth cones and dendritic spines contains solely actin networks and is devoid of microtubules and neurofilaments. Since both these structures contain myosin and since growth cones are endowed with a considerable motility, dendritic spines also may have a likewise property. The necessary regulation of the levels of free cytosolic calcium may be provided by the spine apparatus in addition to calcium pumps in the plasma membrane and calcium regulatory proteins in the spine cytoplasm. Various types of stimulation which change the level of free cytosolic calcium may induce contraction of the spine actin network which may be responsible for the morphometric changes observed following different experimental interventions and pathological conditions. Although most of the conclusions in this review are rather speculative, they may provide directions for future research in the spine and synaptic plasticity.
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Evolution of the intracellular changes in neurons caused by trimethyltin.
Rats have been given a single dose of trimethyltin (10 mg/kg) and the intracellular events have been followed particularly in hippocampus, cerebral cortex, cerebellum and spinal ganglion cells. The earliest change visible occurs 12 h after this dose and is found to be dense membrane-bound bodies, probably derived from branching tubulo-vesicular smooth endoplasmic reticulum formations. These occur in close connection with rought endoplasmic reticulum and polyribosomes and appear also to have some association with the Golgi complex. At 24 h there is a general vacuolation of Golgi cisterns and SER membranes, and the membrane-bound dense body formation is greatly increased. SER abnormalities are particularly conspicuous in Purkinje cells. In spinal ganglion cells, while vacuolation of Golgi cisterns is intense, dense bodies are inconspicuous and are replaced by increased autophagosomes, often of great complexity. By 48 h vacuolation of Golgi cisterns has waned, but accumulation of dense bodies and secondary lysosomes has steadily increased. In spinal ganglion cells autophagosomes only are increased as the Golgi vacuolation declines. At later times steady increases of lysosomal dense bodies is seen generally accompanied in hippocampal pyramidal cells and dentate fascia cells by abundant cell death. The suggestion is put forward that the Golgi complex may be the seat of the critical metabolic lesion and disturbances to protein transfer and protein synthesis follow. No explanation for the selective loss of hippocampal h1-5 (CA1-CA4 except Sommer's sector) pyramidal cells and of small dentate fascia neurons can be derived from these conclusions.
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Developmental gene expression patterns driving species-specific cortical features.
The cerebral cortex shows species-specific variations in size and organization, which probably account for distinct behavioural abilities1. These structural differences may reflect evolutionary changes in the developmental expression of shared genes. Here, to investigate this possibility, we used machine vision to identify and compare cell-type-specific gene expression patterns in the developing mouse and human neocortex, and in human cortical organoids. Using this approach, we identified genes with evolutionarily conserved or divergent transcriptional regulation, revealing species-specific cyto-temporal gene expression patterns. Among such genes, the transcription factor gene JUNB showed mutually exclusive expression in human progenitors and mouse neurons. Through cell-type-specific gain- and loss-of-function experiments in mice and human cortical organoids, we show that JUNB bidirectionally controls human cortical features, including progenitor proliferation rates, neuronal production timing and total neuronal output. We identify IRF1 as a human radial glia-specific regulator that, when expressed in mouse radial glia, activates JUNB and recruits human-like gene regulatory networks, demonstrating cross-species activation of poised developmental programmes. Together, these findings reveal how cyto-temporal regulation of shared genes drives species-specific cortical features, and provide a molecular framework for understanding and manipulating these evolutionary programmes.
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ClusterMap for multi-scale clustering analysis of spatial gene expression.
Quantifying RNAs in their spatial context is crucial to understanding gene expression and regulation in complex tissues. In situ transcriptomic methods generate spatially resolved RNA profiles in intact tissues. However, there is a lack of a unified computational framework for integrative analysis of in situ transcriptomic data. Here, we introduce an unsupervised and annotation-free framework, termed ClusterMap, which incorporates the physical location and gene identity of RNAs, formulates the task as a point pattern analysis problem, and identifies biologically meaningful structures by density peak clustering (DPC). Specifically, ClusterMap precisely clusters RNAs into subcellular structures, cell bodies, and tissue regions in both two- and three-dimensional space, and performs consistently on diverse tissue types, including mouse brain, placenta, gut, and human cardiac organoids. We demonstrate ClusterMap to be broadly applicable to various in situ transcriptomic measurements to uncover gene expression patterns, cell niche, and tissue organization principles from images with high-dimensional transcriptomic profiles.