Human Brain 3d Model Free Download //TOP\\

Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive decline, memory loss, and inability to perform everyday functions. Hallmark features of AD-including generation of amyloid plaques, neurofibrillary tangles, gliosis, and inflammation in the brain-are well defined; however, the cause of the disease remains elusive. Growing evidence implicates pathogens in AD development, with herpes simplex virus type I (HSV-1) gaining increasing attention as a potential causative agent. Here, we describe a multidisciplinary approach to produce physiologically relevant human tissues to study AD using human-induced neural stem cells (hiNSCs) and HSV-1 infection in a 3D bioengineered brain model. We report a herpes-induced tissue model of AD that mimics human disease with multicellular amyloid plaque-like formations, gliosis, neuroinflammation, and decreased functionality, completely in the absence of any exogenous mediators of AD. This model will allow for future studies to identify potential downstream drug targets for treating this devastating disease.

This interactive brain model is powered by the Wellcome Trust and developed by Matt Wimsatt and Jack Simpson; reviewed by John Morrison, Patrick Hof, and Edward Lein.

Structure descriptions were written by Levi Gadye and Alexis Wnuk and Jane Roskams.

Human Brain 3d Model Free Download

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Reference brains are indispensable tools in human brain mapping, enabling integration of multimodal data into an anatomically realistic standard space. Available reference brains, however, are restricted to the macroscopic scale and do not provide information on the functionally important microscopic dimension. We created an ultrahigh-resolution three-dimensional (3D) model of a human brain at nearly cellular resolution of 20 micrometers, based on the reconstruction of 7404 histological sections. "BigBrain" is a free, publicly available tool that provides considerable neuroanatomical insight into the human brain, thereby allowing the extraction of microscopic data for modeling and simulation. BigBrain enables testing of hypotheses on optimal path lengths between interconnected cortical regions or on spatial organization of genetic patterning, redefining the traditional neuroanatomy maps such as those of Brodmann and von Economo.

Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

(a) Microscopic image shows a single colony of H9-GFP+ hESCs (Left), and a representative example of 46-days old GFP+ brain organoids used for the transplantation experiments. (b) Immunofluorescence staining for GFP of GFP-expressing cerebral organoids at day 60. Note, unlike the perimeter areas, the center of the organoid lacks GFP expression. Solid line indicates the border of the low-GFP expressing region. (c) Cerebral organoids immunostained for PAX6 and CTIP2 at 38 days. (d) 38-days old cerebral organoids immunostained for SOX2 and NeuN. Right panel is magnification of the boxed area in the left panel. Scale bar is 1 mm in a, 200 m in b, 20 m in c, d (right), and 200 m in d (left).

(a) Immunofluorescence staining for GFP and human mitochondria (hMito), which specifically labels human cells, of the grafted brain organoid at 14 dpi. Insets show staining form the same section of neurites projection into the host brain. (b) Lower power slide scanner image of a coronal brain section stained with anti-GFP antibody showing robust integration of GFP+ human brain organoids at 90 dpi. Unlike organoids grown in culture before grafting (Supplementary Fig. 1b), there are no detectable signs of regions that lack GFP expression in the center of the organoid 3 months post-implantation. (c) Left, confocal stitched tile scan of 90dpi-organoid graft stained with GFP. Right, Histogram of GFP intensity at various positions of the graft across the red line. Nuclei were counterstained with DAPI. Scale bar is, 100 m in a, 1 mm in b, 200 m in c.

(c) Immunofluorescence staining of GFP, Sox2, and NeuN within the grafted brain organoid at 90 dpi.(d) Immunofluorescence staining of GFP and MAP2 within the grafted brain organoid at 90 dpi. (e) Immunofluorescence staining of GFP, hNuclei, and SOX2 within the grafted brain organoid at 233 dpi. (f) Immunofluorescence staining of GFP and NeuN, within the grafted organoid at 233 dpi. (g) Immunofluorescence staining of GFP, Olig2, and Iba1 within the grafted brain organoid at 233 dpi. (h) Example image of coronal section obtained from grafted mouse brain at 90 dpi. Nuclei were counterstained with DAPI. Scale bar is, 500 m in a, 50 m in b-g, 1 mm in h.

(a) Slide scanner images of coronal brain sections stained for GFP and obtained from 90-dpi grafted mouse brain show robust integration of GFP+ organoids and very large numbers of axons extending into the grafting region and into more rostral section of the host brain. Dashed boxes indicate the sampled region from which higher magnification views in (b) were obtained. Note that images were over-saturated for the signal in the graft region to show the GFP signal in the axons trajectories. Note that the high background on the edge of the section is a nonspecific signal. Scale bars:1 mm in a and 200 m in b.

(a) Double immunofluorescence staining of GFP and the endothelial marker Endoglin in the indicated post-implantation stage showing the intensive growth of blood vessels inside the organoid graft. (b) Double immunofluorescence staining for human-specific CD31 and CD31 (recognizing both mouse and human) of organoid graft harvested at 90 dpi. Note that the organoid graft is negative for human CD31, suggesting a host origin of the infiltrated blood vessels at the examined time point. (c) Quantification of vascularization success rate in the grafted organoids. Average value is 85.4%6.4; data represent means.e.m (n=10 independent experiments, total of 55 animals). (d) Surface area change of single grafted organoids during the first 2 weeks of implantation. (e) The average change of total organoid surface area during the first 2 weeks of implantation normalized to day 0 (100%). Data represent mean s.e.m from at least 3 grafted animals; day 0-5 (n=9), day 6 (n=8), day 7 and 8 (n=6), day 13 (n=4), day 14 (n=3). (f) Deep in vivo two-photon imaging of GFP signal of the implanted organoids in a head-fixed awake mouse through the cranial window, demonstrating the feasibility of the imaging system. Image shows maximum projection of 300 m from 200-500 m inside the grafted organoid from a 30 dpi mouse. (g) Two-photon imaging of blood vessels inside the grafted organoid. Dextran was infused in engrafted animal at 120 dpi. Single z-plane acquired at 418 m depth below the organoid surface, showing blood flow inside the vascular network (see Supplementary video 4). Scale bar is 50 m in a,b and 100 m in h,g.

Examples of in vivo recording from the organoid graft and the host brain. (a-b) Left panels, firing rate changes of single neurons obtained from the indicated time points and the dorsal-ventral (DV) depth from the graft surface. Each line (color-coded) indicates the firing rate of an individual neuron. Arrows on the top denote the time isoflurane was turned ON (filled arrows) and OFF (empty arrows). Right panels, spike raster plots from the neurons in the left panel. Each vertical bar indicates a single spike. (c) Firing rate changes of single neurons obtained from the host cortical region.

Organoid graft was injected with AAV-hSyn-ChR2-YFP and analyzed at 155 dpi. (a) Immunostaining for GFP (labeling hSyn::ChR2-YFP) and hNuclei inside the organoid graft. (b) Immunostaining for tdTomato (labeling organoid graft) and GFP (labeling hSyn::ChR2-YFP) in the cortex of the host brain at 155 dpi. Bottom panels are magnification of the boxed area in the top panel. Note the fragmented tdTomato expression along the axons perhaps due to long term expression. Nuclei were counterstained with DAPI. Scale bar is 50 m.

(a) Diagram of optogenetic stimulation in tdTomato-expressing uninfected-control organoid and electrophysiological recording in the host brain. (b) Local field potential (LFP) recorded from a single electrode in the control host brain after optogenetic stimulation of organoid with 20 Hz light stimulation. The voltage is color coded for 30 trials (top). Averaged LFP across trials (bottom). (c) LFP changes recorded from a different electrode from the same brain region in (b). (d-h) Organoid graft was injected with AAV-hSyn-ChR2-YFP and analyzed at 155dpi. (d) Diagram of optogenetic stimulation in tdTomato-expressing, AAV-hSyn-ChR2-YFP-infected, organoid and electrophysiological recording in the host brain (fiber location: DV -1.7mm; array location: AP -2.54 mm, ML -1.5 mm, DV -2.2 mm). (e) Local field potential recorded from a single electrode in the host brain region. Optogenetic stimulation of organoid with 20 Hz drives LFP changes in the host brain region. The voltage is color coded for 30 trials (top). Averaged LFP across trials (bottom). Inset: Averaged LFP with a finer time scale. (f) Power spectral density of the averaged LFP in (e). (g) LFP changes recorded from a different electrode from the same brain region in (e). Inset: Averaged LFP with a finer time scale. (h) Power spectral density of the averaged LFP in (g). (i-k) LFP changes recorded from the same animal and brain region as in (d) but from different, more dorsal array location (AP -2.54 mm, ML -1.5 mm, DV -0.8mm). n=2 animals. All recordings were performed while animals were under isoflurane anesthesia. ff782bc1db