A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution

Shapson-Coe, Alexander; Januszewski, Michał; Berger, Daniel R.; Pope, Art; Wu, Yuelong; Blakely, Tim; Schalek, Richard L.; Li, Peter H.; Wang, Shuohong; Maitin-Shepard, Jeremy; Karlupia, Neha; Dorkenwald, Sven; Sjostedt, Evelina; Leavitt, Laramie; Lee, Dongil; Troidl, Jakob; Collman, Forrest; Bailey, Luke; Fitzmaurice, Angerica; Kar, Rohin; Field, Benjamin; Wu, Hank; Wagner-Carena, Julian; Aley, David; Lau, Joanna; Lin, Zudi; Wei, Donglai; Pfister, Hanspeter; Peleg, Adi; Jain, Viren; Lichtman, Jeff W.

doi:10.1126/science.adk4858

Cited by 72 publications

(4 citation statements)

References 84 publications

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“…The neuronal density in human is approximately 0.1 x 10 5 to 0.5 x 10 5 neurons/mm 3 , which is substantially lower than in rodent (Gittins and Harrison, 2004; Gredal et al, 2000). A recent EM study reports that the percentage of neurons in human cortex is 40-65% in L2-L4 and 20-30% in L5-L6 (Shapson-Coe et al, 2024). A neuronal density of 0.2 x 10 5 neurons/mm 3 is reported for pig visual cortex, which is comparable to that of human (Cragg, 1967).…”

Section: Discussionmentioning

confidence: 99%

“…In our case the tools deliver a coarse layout of the vessel pattern but that requires a serious workover by trained examiners because e. g. thin vessel connections would have been missed. A similar note towards involving the best hightech available, the human retina and brain, has been given for working with automated serial reconstructions of EM images (Shapson-Coe et al, 2024; Wu et al, 2024).…”

Section: Methodsmentioning

confidence: 99%

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Vascular development of fetal and postnatal neocortex of the pig, the European wild boarSus scrofa

Sobierajski,

Czubay,

Beemelmans

et al. 2024

Preprint

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The development of the brains vascular system is a predominantly prenatal process in mammalian species and required for neurogenesis and further brain development. Our recent work on fetal pig has revealed that many neurodevelopmental processes start well before birth and proceed rapidly reaching near-mature status already around birth. Here, we analyzed the development of neocortical vasculature from embryonic day (E) 45 onwards (gestation in pig lasts 114 days) using qualitative and quantitative image analyses and protein blots. In all cortical layers, vessel volume from total brain volume at E100 resembled that of a postnatal day (P) 30 piglet. Endothelial cells expressed the tight junction protein claudin-5 from E45 onwards. GFAP+ and AQP4+ astrocytes, PDGFRβ+ pericytes and α-SMA+ smooth muscle cells are detectable near vessels at E60 suggesting an early assembly of blood-brain barrier components. The vascular system in the visual cortex is advanced before birth with an almost mature pattern at E100. Findings were confirmed by blots which showed a steady increase of expression of tight junction and angiogenesis-related proteins (claudin-5, occludin, VE-cadherin, PECAM-1/CD31) from E65 onwards until P90. The expression profile was similar in visual and somatosensory cortex. Together, we report a rapid maturation of the vascular system in pig cortex. Regarding activity-dependent aspects, the data suggest that angiogenesis might be influenced by spontaneous rather than sensory-evoked activity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Vascular development of fetal and postnatal neocortex of the pig, the European wild boarSus scrofa

Sobierajski,

Czubay,

Beemelmans

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, synapses in the neuropil are sometimes classified as excitatory or inhibitory on the basis of whether they synapse onto dendritic spines or shafts, respectively 21 , 22 , 44 , 45 , and they are annotated manually or using machine learning tools to train automated synapse classifiers to identify the pre- and postsynaptic component of each synapse (e.g., ref. 46 ). However, in our present study, the identification of synapses is based on the classical definition of synaptic contacts visualized at high resolution in serial sections.…”

Section: Discussionmentioning

confidence: 99%

Tracing nerve fibers with volume electron microscopy to quantitatively analyze brain connectivity

Turegano-Lopez,

de las Pozas,

Santuy

et al. 2024

Commun Biol

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The highly complex structure of the brain requires an approach that can unravel its connectivity. Using volume electron microscopy and a dedicated software we can trace and measure all nerve fibers present within different samples of brain tissue. With this software tool, individual dendrites and axons are traced, obtaining a simplified “skeleton” of each fiber, which is linked to its corresponding synaptic contacts. The result is an intricate meshwork of axons and dendrites interconnected by a cloud of synaptic junctions. To test this methodology, we apply it to the stratum radiatum of the hippocampus and layers 1 and 3 of the somatosensory cortex of the mouse. We find that nerve fibers are densely packed in the neuropil, reaching up to 9 kilometers per cubic mm. We obtain the number of synapses, the number and lengths of dendrites and axons, the linear densities of synapses established by dendrites and axons, and their location on dendritic spines and shafts. The quantitative data obtained through this method enable us to identify subtle traits and differences in the synaptic organization of the samples, which might have been overlooked in a qualitative analysis.

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“…Modern bidomain models [44], [45] could possibly resolve this issue. The next logical yet extremely challenging step is to analyze the much larger 1mm 3 MICrONS mouse brain sample [40], which includes a considerably better-developed axonal arbor and ~75,000 neuronal cells, and other very recent large brain samples [41]. This would require further improvement of the computational method.…”

Section: Other Limitations Of This Studymentioning

confidence: 99%

Enabling Electric Field Model of Microscopically Realistic Brain

Qi,

Noetscher,

Miles

et al. 2024

Preprint

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Across all electrical stimulation (neuromodulation) domains, conventional analysis of cell polarization involves two discrete steps: i) prediction of tissue electric field ignoring presence of cells and; ii) prediction of cell polarization from tissue electric fields. The first step assumes that electric current flow is not distorted by the dense tortuous network of cell structures. The deficiencies of this assumption have long been recognized, but – except for trivial geometries – ignored, because it presented intractable computation hurdles.We leverage recent electron microscopic images of the brain that have made it possible to reconstruct microscopic brain networks over relatively large volumes and a charge-based formulation of boundary element fast multipole method (BEM-FMM) for the first stimulations of realistic neuronal polarization by electrical stimulation that consider field distortions by a cellular network. The dataset under study is a 250×140×90 μm section of the L2/L3 mouse visual cortex with 396 tightly spaced neurite cells and 34 microcapillaries. We report that brain microstructure significantly distorts the primary macroscopic electric field. Although being very local such distortions constructively accumulate along the neuronal arbor and reduce neuronal activating thresholds by 0.55-0.85-fold as compared to conventional theory.Significance statementThis study introduces a novel method for modeling perturbations of impressed electric fields within a microscopically realistic brain volume, with densely populated neuronal cells and blood microcapillaries. It addresses the limitation of present macroscopic-level electromagnetic models in brain stimulation, which predict 2.5–3 times higher activating thresholds than those observed in experiments. Despite the challenge posed by the small size of the brain sample, our model predicted a consistent average threshold reduction factor of 0.85–0.55 when compared to the macroscopic approach. The present study begins to bridge a critical gap in our understanding of neural activation and arguably creates a new standard for future research in neuronal network modeling in brain stimulation and electrophysiology.

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A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution

Cited by 72 publications

References 84 publications

Vascular development of fetal and postnatal neocortex of the pig, the European wild boarSus scrofa

Vascular development of fetal and postnatal neocortex of the pig, the European wild boarSus scrofa

Tracing nerve fibers with volume electron microscopy to quantitatively analyze brain connectivity

Enabling Electric Field Model of Microscopically Realistic Brain

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