Abstract
Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of ∼20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zapala, M. A. et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl Acad. Sci. USA 102, 10357–10362 (2005)
Datson, N. A., van der Perk, J., de Kloet, E. R. & Vreugdenhil, E. Expression profile of 30,000 genes in rat hippocampus using SAGE. Hippocampus 11, 430–444 (2001)
Sandberg, R. et al. Regional and strain-specific gene expression mapping in the adult mouse brain. Proc. Natl Acad. Sci. USA 97, 11038–11043 (2000)
Siddiqui, A. S. et al. A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells. Proc. Natl Acad. Sci. USA 102, 18485–18490 (2005)
Kamme, F. et al. Single-cell microarray analysis in hippocampus CA1: demonstration and validation of cellular heterogeneity. J. Neurosci. 23, 3607–3615 (2003)
Sugino, K. et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nature Neurosci. 9, 99–107 (2006)
Markram, H. et al. Interneurons of the neocortical inhibitory system. Nature Rev. Neurosci. 5, 793–807 (2004)
Toledo-Rodriguez, M., Goodman, P., Illic, M., Wu, C. & Markram, H. Neuropeptide and calcium-binding protein gene expression profiles predict neuronal anatomical type in the juvenile rat. J. Physiol. (Lond.) 567, 401–413 (2005)
Monyer, H. & Markram, H. Interneuron diversity series: Molecular and genetic tools to study GABAergic interneuron diversity and function. Trends Neurosci. 27, 90–97 (2004)
Christiansen, J. H. et al. EMAGE: a spatial database of gene expression patterns during mouse embryo development. Nucleic Acids Res. 34, D637–D641 (2006)
Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003)
Visel, A., Thaller, C. & Eichele, G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 32, D552–D556 (2004)
Gray, P. A. et al. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306, 2255–2257 (2004)
Magdaleno, S. et al. BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system. PLoS Biol. 4, e86 (2006)
Boguski, M. S. & Jones, A. R. Neurogenomics: at the intersection of neurobiology and genome sciences. Nature Neurosci. 7, 429–433 (2004)
Dennis, G. et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4, P3 (2003)
Kirkwood, A., Rioult, M. C. & Bear, M. F. Experience-dependent modification of synaptic plasticity in visual cortex. Nature 381, 526–528 (1996)
Elias, C. F. et al. Characterization of CART neurons in the rat and human hypothalamus. J. Comp. Neurol. 432, 1–19 (2001)
Heuer, H. et al. Connective tissue growth factor: a novel marker of layer VII neurons in the rat cerebral cortex. Neuroscience 119, 43–52 (2003)
Zola-Morgan, S., Squire, L. R. & Amaral, D. G. Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J. Neurosci. 6, 2950–2967 (1986)
Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. 1957. J. Neuropsychiatry Clin. Neurosci. 12, 103–113 (2000)
Lorente de Nó, R. Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J. Psychol. Neurol. (Lpz.) 46, 113–177 (1934)
Amaral, D. G. & Witter, M. P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989)
Ishizuka, N., Weber, J. & Amaral, D. G. Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat. J. Comp. Neurol. 295, 580–623 (1990)
Tole, S., Christian, C. & Grove, E. A. Early specification and autonomous development of cortical fields in the mouse hippocampus. Development 124, 4959–4970 (1997)
Lein, E. S., Zhao, X. & Gage, F. H. Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. J. Neurosci. 24, 3879–3889 (2004)
Yamagata, M., Sanes, J. R. & Weiner, J. A. Synaptic adhesion molecules. Curr. Opin. Cell Biol. 15, 621–632 (2003)
Small, S. A. The longitudinal axis of the hippocampal formation: its anatomy, circuitry, and role in cognitive function. Rev. Neurosci. 13, 183–194 (2002)
Moser, M. B. & Moser, E. I. Functional differentiation in the hippocampus. Hippocampus 8, 608–619 (1998)
Bannerman, D. M. et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci. Biobehav. Rev. 28, 273–283 (2004)
Voogd, J., Hess, D. & Marani, E. The Parasagittal Zonation of the Cerebellar Cortex in Cat and Monkey: Topography, Distribution of Acetylcholinesterase, and Development (ed. King, E. S.) (Liss, New York, 1987)
Herrup, K. & Kuemerle, B. The compartmentalization of the cerebellum. Annu. Rev. Neurosci. 20, 61–90 (1997)
Hawkes, R. & Herrup, K. Aldolase C/zebrin II and the regionalization of the cerebellum. J. Mol. Neurosci. 6, 147–158 (1995)
Gravel, C. & Hawkes, R. Parasagittal organization of the rat cerebellar cortex: direct comparison of Purkinje cell compartments and the organization of the spinocerebellar projection. J. Comp. Neurol. 291, 79–102 (1990)
Blackshaw, S. & Snyder, S. H. Encephalopsin: a novel mammalian extraretinal opsin discretely localized in the brain. J. Neurosci. 19, 3681–3690 (1999)
Eberwine, J., Belt, B., Kacharmina, J. E. & Miyashiro, K. Analysis of subcellularly localized mRNAs using in situ hybridization, mRNA amplification, and expression profiling. Neurochem. Res. 27, 1065–1077 (2002)
Kang, H. & Schuman, E. M. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273, 1402–1406 (1996)
Huber, K. M., Kayser, M. S. & Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288, 1254–1257 (2000)
Burgin, K. E. et al. In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J. Neurosci. 10, 1788–1798 (1990)
Trapp, B. D. et al. Spatial segregation of mRNA encoding myelin-specific proteins. Proc. Natl Acad. Sci. USA 84, 7773–7777 (1987)
Kindler, S., Wang, H., Richter, D. & Tiedge, H. RNA transport and local control of translation. Annu. Rev. Cell Dev. Biol. 21, 223–245 (2005)
Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005)
Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002)
Vavouri, T. & Elgar, G. Prediction of cis-regulatory elements using binding site matrices—the successes, the failures and the reasons for both. Curr. Opin. Genet. Dev. 15, 395–402 (2005)
Luquet, S., Perez, F. A., Hnasko, T. S. & Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005)
Lechner, H. A., Lein, E. S. & Callaway, E. M. A genetic method for selective and quickly reversible silencing of Mammalian neurons. J. Neurosci. 22, 5287–5290 (2002)
Yoshihara, Y. et al. A genetic approach to visualization of multisynaptic neural pathways using plant lectin transgene. Neuron 22, 33–41 (1999)
DeFalco, J. et al. Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science 291, 2608–2613 (2001)
Brecht, M. et al. Novel approaches to monitor and manipulate single neurons in vivo. J. Neurosci. 24, 9223–9227 (2004)
Ng, L. et al. Neuroinformatics for genome-wide 3-D gene expression mapping in the mouse brain. IEEE Trans. Comput. Biol. Bioinform. (in the press).
Thompson, P. M. & Toga, A. W. in Handbook of Medical Imaging: Processing and Analysis (ed. Bankman, I. N.) (Academic Press, San Diego, 2000)
Viola, P. & Wells, W. M. Alignment by maximization of mutual information. Int. J. Comput. Vis. 24, 137–154 (1997)
Chan, T. F. & Shen, J. Image Processing and Analysis: Variation, PDE, Wavelet, and Stochastic Methods (Society for Industrial and Applied Mathematics, Philadelphia, 2005)
Lein, E. S., Callaway, E. M., Albright, T. D. & Gage, F. H. Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J. Comp. Neurol. 485, 1–10 (2005)
Swanson, L. W. Brain Maps: Structure of the Rat Brain (Elsevier, Amsterdam, 2004)
Acknowledgements
This work was sponsored by the Allen Institute for Brain Science. The authors wish to thank the Allen Institute founders, P. G. Allen and J. Patton, for their vision, encouragement and support. We also wish to thank key Institute advisors, K. Dooley and S. Coliton, as well as the Scientific Advisory Board for the Atlas project, M. Tessier-Lavigne, D. Anderson, C. Dulac, R. Gibbs, S. Paul, G. Schuler, A. W. Toga and J. Takahashi, for their scientific guidance and dedication to the successful execution of the Atlas project. We would particularly like to acknowledge D. Anderson for his role in the conceptual genesis and continual refinement of Atlas goals, as well as M. Tessier-Lavigne for key scientific and organizational leadership throughout the project. We also thank C. Jennings for his critical reading of the manuscript.
Author Contributions Neuroscience Group: E.S.L. (group leader), A.B., L.C., M.P.H., M.T.M, C.L.T., T.A.Z. Informatics Group: M.J.H. (group leader), C.L.K., C.L., L.L.N., S.D.P. Production Groups: Allen Institute for Brain Science: P.E.W. (group leader), S.M.S. (group leader), R.A.J. (group leader), M.A., A.F.B., E.J.B., S.D., N.R.D., A.L.D., T.D., E.D., M.J.D., J.G.D., A.J.E., L.K.E., S.R.F., S.N.G., K.J.G., K.R.H., M.R.H., J.M.K., R.H.K., J.H.L., T.A.L., L.T.L., R.J.M., N.F.M., R.N., G.J.O., T.H.P., S.E.P., O.C.P., R.B.P., Z.L.R., H.R.R., S.A.R., J.J.R., N.R.S., K.S., N.V.S., T.S., C.R.S., S.C.S., K.A.S., N.N.S., K.-R.S., L.R.V., R.M.W., C.K.W., V.Y.W., X.F.Y.; Baylor College of Medicine: C.T. (group leader), N.A., L.C. (Li Chen), T.-M.C., A.C., R.F., A.J.L., Y.L., M.J.R., A.T., M.W., M.B.Y., B.Z.; Max Planck Institute: G.E. (group leader), A.V. Technology Group: C.N.D. (group leader), C.D.T. (group leader), A.B. (Amy Bensinger), K.S.B., M.C.C., J.C., B.E.C., T.A.D., B.J.D., T.P.F., C.F. (Cliff Frensley), D.P.J., P.T.K., R.K., A.R.L., K.D.L., J.M., B.I.S., A.J.S., M.S., R.C.Y., B.L.Y. Other: H.-W.D., B.A.F., C.F. and J.J.M., Allen Reference Atlas generation; J.G.H., data annotation; C.C.O., critical review and manuscript preparation; M.S.B., overall project leadership 2003–2004; A.R.J., overall project leadership 2004–present.
Disclaimer The Nature Publishing Group has a business collaboration with the Allen Institute for the creation and maintenance of the Neuroscience gateway (http://www.brainatlas.org), but has no role in generating or curating the Allen Brain Atlas database content. As always, Nature Editors have been fully independent and solely responsible for the editorial content and peer review of this research article.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Supplementary information
Supplemental Methods 1
Detailed methodologies for tissue processing, probe design and generation, data generation, and image acquisition used for the Allen Brain Atlas project (PDF 1587 kb)
Supplemental Methods 2
Detailed methodologies for informatics-based image quantification and mapping of ISH data to a common 3D coordinate system for genome-wide analysis (DOC 25603 kb)
Supplemental Methods 3
Detailed methodologies used to generate the Allen Reference Atlas (PDF 559 kb)
Supplemental Methods 4
Description of methods used for voxel-based correlation analysis (DOC 41 kb)
Supplemental Data 1
Comparison of non-isotopic in situ hybridization (ISH) data generated for the Allen Brain Atlas project to comparable radioactive ISH data from other sources (DOC 2418 kb)
Supplemental Data 2
Side-by-side image comparison of non-isotopic in situ hybridization (ISH) data generated for the Allen Brain Atlas project to comparable radioactive ISH data. Accompanies Supplemental Data 1 (PDF 19230 kb)
Supplemental Data 3
Control data demonstrating the reproducibility of the ABA ISH platform across conditions and across the duration of the ABA project (PDF 4775 kb)
Supplemental Data 4
Comparison of expression patterns of the ligand-gated ion channel family to available literature and other data sources, as well as methodology for fine-detailed expert annotation of the ligand-gated ion channel family in the neocortex (DOC 412 kb)
Supplemental Data 5
Detailed expert annotation of the complete ligand-gated ion channel family in layers of the neocortex. Accompanies Supplemental Data 4 (XLS 44 kb)
Supplemental Figure 1
Genome-wide analysis of expression level vs. percentage of expressing cells in 12 major brain regions (JPG 840 kb)
Supplementary Table 1
Genes enriched in major cell populations in the brain (neurons, oligodendrocytes, astrocytes, and choroid plexus cells) identified through correlation-based searches seeded with cell-type specific gene expression patterns. Also included are genes with apparent ubiquity as well as genes that do not have detectable expression in the brain (XLS 184 kb)
Supplemental Table 2
Gene Ontology (GO) categories over-represented in genes enriched in major neural cell types and in genes that are either apparently ubiquitous or not expressed. Accompanies Supplemental Table 1 (XLS 612 kb)
Supplemental Table 3
Genes identified as the most specific for each of 12 different major brain regions (XLS 198 kb)
Supplemental Table 4
Genes displaying mRNA targeting to dendrites (neurons) or processes (non-neuronal cells) (XLS 37 kb)
Rights and permissions
About this article
Cite this article
Lein, E., Hawrylycz, M., Ao, N. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007). https://doi.org/10.1038/nature05453
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature05453
