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      A cellular resolution atlas of Broca’s area

      research-article
      1 , 2 , 3 , * , , 4 , 5 , 4 , 6 , 4 , 6 , 1 , 1 , 7 , 8 , 1 , 3 , 7 , 1 , 7 , 1 , 7 , 9 , 9 , 1 , 3 , 7 , 10 , 10 , 10 , 10 , 11 , 5 , 4 , 6 , 4 , 4 , 4 , 4 , 6 , 4 , 6 , 4 , 6 , 12 , 13 , 4 , 4 , 6 , 4 , 6 , 14 , 15 , 4 , 13 , 16 , 4 , 6 , 4 , 6 , 4 , 6 , 17 , 18 , 5 , 1 , 3 , 7 , 4 , 6 , 13 , 19 , 10
      Science Advances
      American Association for the Advancement of Science

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          Abstract

          Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)–referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with a digital stereological approach on the 3D reconstruction at cellular resolution from a custom-made inverted confocal light-sheet fluorescence microscope (LSFM). Mesoscale optical coherence tomography enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system. The outcome is an integrated high-resolution cellular census of Broca’s area in a human postmortem specimen, within a whole-brain reference space atlas.

          Abstract

          Advancements in imaging and analysis enable the construction of a cellular atlas of the human cerebral cortex.

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          Most cited references55

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          Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia.

          Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Single-cell genomics identifies cell type–specific molecular changes in autism

            Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.
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              Structural and molecular interrogation of intact biological systems.

              Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Validation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: SoftwareRole: Visualization
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Visualization
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: Writing - review & editing
                Role: Resources
                Role: Data curationRole: InvestigationRole: Visualization
                Role: Formal analysisRole: Investigation
                Role: VisualizationRole: Writing - review & editing
                Role: InvestigationRole: Project administration
                Role: Formal analysisRole: InvestigationRole: SoftwareRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: ResourcesRole: Validation
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: Software
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: Investigation
                Role: MethodologyRole: SoftwareRole: Writing - review & editing
                Role: InvestigationRole: Project administrationRole: ResourcesRole: SoftwareRole: Validation
                Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: Resources
                Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Visualization
                Role: Project administration
                Role: Formal analysisRole: MethodologyRole: Software
                Role: Resources
                Role: MethodologyRole: Software
                Role: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: InvestigationRole: SoftwareRole: Writing - review & editing
                Role: MethodologyRole: ResourcesRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                13 October 2023
                12 October 2023
                : 9
                : 41
                : eadg3844
                Affiliations
                [ 1 ]European Laboratory for Non-Linear Spectroscopy (LENS), University of Florence, Sesto Fiorentino (FI), Italy.
                [ 2 ]Department of Biology, University of Florence, Florence, Italy.
                [ 3 ]National Institute of Optics (INO), National Research Council (CNR), Sesto Fiorentino, Italy.
                [ 4 ]Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.
                [ 5 ]Department of Biomedical Engineering, Boston University, Boston, MA, USA.
                [ 6 ]Department of Radiology, Harvard Medical School, Boston, MA, USA.
                [ 7 ]Department of Physics and Astronomy, University of Florence, Sesto Fiorentino (FI), Italy.
                [ 8 ]Division of Physiology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
                [ 9 ]Bioretics srl, Cesena, Italy.
                [ 10 ]Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [ 11 ]Department of Electrical and Computer Engineering, Boston University, Boston, MA, USA.
                [ 12 ]Department of Medical Physics and Biomedical Engineering, University College London, London, UK.
                [ 13 ]Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
                [ 14 ]Imaging Science Program, Washington University McKelvey School of Engineering, St. Louis, MO, USA.
                [ 15 ]Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
                [ 16 ]C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
                [ 17 ]Department of Human Biology, University of Cape Town, Cape Town, South Africa.
                [ 18 ]Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, Hong Kong.
                [ 19 ]HST, Massachusetts Institute of Technology, Cambridge, MA, USA.
                Author notes
                [* ]Corresponding author. Email: costantini@ 123456lens.unifi.it
                [†]

                These authors contributed equally to this work.

                [‡]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-8464-7324
                https://orcid.org/0000-0001-6859-734X
                https://orcid.org/0000-0001-8758-9978
                https://orcid.org/0000-0002-3517-9739
                https://orcid.org/0000-0002-5863-399X
                https://orcid.org/0000-0003-2438-2923
                https://orcid.org/0000-0003-3077-3904
                https://orcid.org/0000-0001-7734-7828
                https://orcid.org/0000-0001-8170-8905
                https://orcid.org/0000-0002-7554-4470
                https://orcid.org/0000-0001-9215-9104
                https://orcid.org/0000-0002-7473-5558
                https://orcid.org/0000-0003-3859-8442
                https://orcid.org/0000-0002-1517-3903
                https://orcid.org/0000-0003-3416-7290
                https://orcid.org/0000-0003-0181-5845
                https://orcid.org/0000-0003-2846-4571
                https://orcid.org/0000-0003-2854-8775
                https://orcid.org/0000-0001-7215-9107
                https://orcid.org/0000-0002-3178-1300
                https://orcid.org/0000-0002-4241-408X
                https://orcid.org/0000-0001-7569-173X
                https://orcid.org/0000-0003-1524-6698
                https://orcid.org/0000-0002-3129-6671
                https://orcid.org/0000-0003-1334-1923
                https://orcid.org/0000-0002-8422-0136
                https://orcid.org/0000-0002-3940-9861
                https://orcid.org/0000-0003-4244-7380
                https://orcid.org/0000-0002-2849-9240
                https://orcid.org/0000-0002-4935-8412
                https://orcid.org/0000-0002-6709-7711
                https://orcid.org/0000-0002-2413-1115
                https://orcid.org/0000-0002-3208-1154
                Article
                adg3844
                10.1126/sciadv.adg3844
                10569704
                37824623
                1f9dbc5a-88ab-4776-b3a4-3100f6b88f35
                Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 20 December 2022
                : 03 May 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000135, NIH Blueprint for Neuroscience Research;
                Award ID: U01 MH093765
                Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;
                Award ID: R21 HD106038
                Funded by: FundRef http://dx.doi.org/10.13039/100010663, H2020 European Research Council;
                Award ID: Starting Grant 677697, project BUNGEE-TOOLS
                Funded by: The National Institute of Health;
                Award ID: R01 AG070988-01 and RF1 MH123195-01
                Funded by: Marie Skłodowska-Curie Grant Agreement;
                Award ID: No. 793849
                Funded by: The National Institute of Mental Health;
                Award ID: R01 MH123195, R01 MH121885, RF1 MH123195
                Funded by: European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement;
                Award ID: No. 785907, No. 945539
                Funded by: BRAIN Initiative Cell Census Network grant;
                Award ID: U01 MH117023
                Funded by: The National Institute on Aging;
                Award ID: R56 AG064027, R01 AG064027, R01 AG008122, R01 AG016495
                Funded by: The National Institute for Neurological Disorders and Stroke;
                Award ID: R01 NS0525851, R21 NS072652, R01 NS070963, R01 NS083534, U01 NS086625, U24 NS10059103, R01 NS105820, R01 NS128843
                Funded by: Shared Instrumentation Grants;
                Award ID: S10 RR023401, S10 RR019307, and S10 RR023043
                Funded by: Italian Ministry for Education in the framework of Euro-Bioimaging Italian Node;
                Award ID: ESFRI research infrastructure
                Funded by: The National Institute for Biomedical Imaging and Bioengineering;
                Award ID: P41 EB015896, R01 EB023281, R01 EB006758, R21E B018907, R01 EB019956, P41 EB030006, R00 EB023993
                Funded by: Chan-Zuckerberg Initiative DAF an advised fund of Silicon Valley Community Foundation grant number;
                Award ID: 2019-198101
                Funded by: European Union’s Horizon 2020 research and innovation Framework Programme under grant agreement;
                Award ID: No. 654148
                Funded by: Alzheimer’s Research UK (Interdisciplinary grant );
                Award ID: ARUK-IRG2019A-003
                Funded by: "Fondazione CR Firenze" (private foundation);
                Award ID: Human Brain Optical Mapping
                Categories
                Research Article
                Neuroscience
                SciAdv r-articles
                Neuroscience
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                Eunice Ann Alesin

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