Sebastian Bludau

A missense variant in SLC1A3 , which results in a proline to arginine substitution in the glial excitatory amino acid transporter 1 (EAAT1), causes a severe form of episodic ataxia type 6, characterized by recurrent attacks of ataxia and epilepsy. EAATs are dual function transport proteins, and the P290R variant reduces secondary active glutamate transport rates, while enhancing the anion channel activity. Here, we used complementary electrophysiological, imaging, biochemical and neuropathological techniques to characterize the cellular mechanisms underlying epileptic seizures in a mouse model of episodic ataxia type 6, the heterozygous Slc1a3 ^P290R/+ mouse. Video-EEG recordings demonstrate frequent and severe spontaneous epileptic seizures in vivo. “Gliosis only” phenotype in the cerebrum of Slc1a3 ^{P290R/ +} mice, which was restricted to the hippocampal formation, suggests that this brain structure may be involved in the development of epileptic seizure activity. Electrophysiological recordings from acute slices revealed a reduction in tonic GABAergic transmission in Slc1a3 ^P290R/+ dentate gyrus granule cells, and to a lesser extent in cortical layer 2/3 pyramidal neurons before seizure onset. Phasic GABAergic and glutamatergic transmission remained unaltered in juvenile animals of the same developmental stage. There was no difference in expression levels of the GABA _A receptor (GABA _A R) δ subunits, suggesting that impaired tonic inhibition results from decreased extrasynaptic GABA concentrations. We identified enhanced GABA uptake by hippocampal radial glia-like cells (RGLs), caused by elevated GABA transporter 3 (GAT-3) expression and by an increased GABA transport driving force—due to lower intracellular chloride levels [Cl ^– ] _int – as cellular basis of impaired tonic inhibition. Our study demonstrates how increased EAAT1 chloride channel activity of the P290R variant can cause hyperexcitability by modifying synaptic GABA concentrations, while impaired EAAT1 glutamate transport leaves glutamatergic synaptic transmission in Slc1a3 ^P290R/+ mice unaffected.

Computational technology opens new possibilities toward understanding the complexity of the human brain, but it requires integrating measurements from different modalities and scales in an anatomical context and exposing them in an interoperable, actionable form. Especially with growing big data resources, accessing information from different scales and modalities coherently for visual exploration, reproducible analysis and application development remains challenging. Here we present siibra, a tool suite that connects diverse data from cloud resources to reference atlases and coordinate spaces. It supports different use cases by making contents accessible through a web viewer, Python library and HTTP application programming interface. Using siibra we implemented a Multilevel Human Brain Atlas linking macro-anatomical concepts and their inter-subject variability with measurements of the microstructural composition and intrinsic variance of brain regions, building on cytoarchitecture as a reference and supporting MRI-based and microscopic templates. The atlas is integrated with the EBRAINS research infrastructure. All software and content are openly accessible.

The human Bed nucleus of the Stria terminalis is a basal forebrain structure and a key player in stress response and anxiety perception. It is a heterogenous structure and consists of distinct subdivisions. However, subdivisions are not visible in routine MR imaging due to low contrast and small size, which makes the exact assignment and identification in images of the living brain difficult or even impossible. Here, we mapped the Bed nucleus in serial, cell body-stained sections of 10 human brains in its full extent, resulting in 1130 annotations. Four subdivisions, a central, dorsal, medial, and a posterior part were identified. Texture analysis was applied to further characterize the subdivisions. Two sets of maps were generated: (1) Probabilistic cytoarchitectonic maps of the Bed nucleus in MNI space, which consider interindividual variability among the brains; (2) Ultra-high-resolution maps of the four subdivisions in the BigBrain 3D histology dataset, to capture complex shape and topology at microscopical level. The maps are openly available, to serve as anatomical reference to neuroimaging studies in healthy subjects and patients and inform modeling and simulation.

The premotor cortex is involved in a variety of motor and cognitive functions that often cannot be unambiguously linked to its microstructural correlates. We re-analysed the cytoarchitecture of this region in ten post mortem brains using an observer-independent mapping approach. Seven areas (6d1-6d3, 6v1-6v3, 6r1) were identified. Based on their cytoarchitectonic similarity, they were grouped into three dorsal (6d1-3) and four ventral (6v1-3, 6r1) premotor areas, supporting the concept of a functionally distinct dorsal and ventral premotor cortex. The superior frontal sulcus was identified as landmark for this separation. Comparison of the new maps with functional studies indicates that the frontal and inferior frontal eye fields are located within the premotor cortex, specifically in areas 6v1 and 6v2, not in the prefrontal cortex. Functional profiles of the areas were determined, serving as an initial basis for a more detailed characterisation of the individual areas. The new maps are publicly available to inform neuroimaging studies and aiding clinical applications such as targeting lesions or tumors and avoiding motor or cognitive impairments.

The mesial piriform region plays a central role in olfaction. Its small size and complex geometry, however, make it a difficult target in functional neuroimaging studies, while histological maps often represent schematic drawings, which are not compatible with requirements for modern imaging. To bridge this gap, cytoarchitectonic analysis and mapping of the region was performed in serial histological sections over their full extent in 10 postmortem brains. The temporobasal areas PirTBd and PirTBv and temporal areas PirTu and PirTit were identified and analyzed. Probabilistic cytoarchitectonic maps of the piriform areas in MNI reference space and high-resolution maps of the amygdala-piriform region on the BigBrain model were calculated as part of the Julich-Brain. Differences in the cytoarchitectonic “texture” of the region were quantified based on the Gray Level Co-Occurrence Matrix. Results showed that allocortical areas were not consistently associated with the rostral Limen insulae, although it was often suggested as a landmark in neuroimaging protocols. PirTu was associated with the uncal tip. PirTit was the largest area, reaching to the temporal pole, with a “temporal” (caudal) and a “temporopolar” (rostral) part having complex neighborhood relationships. The probabilistic maps reflect interindividual variability; they are openly available via the digital EBRAINS platform to serve as an anatomical reference for studies related to olfaction.

A present-day atlas of the human brain: Defining brain regions and demarking their spatial extent are important goals in neuroscience. A modern map of the brain's cellular structure, a cytoarchitectonic atlas, should provide maps of areas in three dimensions, integrate recent knowledge about brain parcellation, consider variations between individual brains, rely on reproducible workflows, and provide web-based links to other resources and databases. Amunts et al. created such an atlas based on serial histological sections of brain. They developed a computational framework and refined the current boundaries of the human brain based on cytoarchitectural patterns. This technique can easily be transferred to build brain atlases for other species or a spatial framework for other organs, other modalities, or multimodal maps for regions of interest at higher spatial scales. This research makes similar future attempts simultaneously reproducible and flexible. Science , this issue p. 988

Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.