If I only had a brain: exploring mouse brain images in the Allen Brain Atlas

Biol. Cell (2007) 99, 403–409 (Printed in Great Britain) doi:10.1042/BC20070031 Scientiae forumMy Favourite Site

If I only had a brain: exploringmouse brain images in the AllenBrain AtlasHarry Hochheiser*1 and Judith Yanowitz†*Department of Computer and Information Sciences, Towson University, 7800 York Road, Suite 406, Towson, MD 21252, U.S.A.,

and †Department of Embryology, Carnegie Institution of Washington, 3520 San Martin Drive, Baltimore, MD 21218, U.S.A.

The combination of a powerful well-designed user interface with detailed high-quality data sets can create newpossibilities for data exploration and analysis. The Allen Brain Atlas (http://www.brain-map.org) provides a collectionof tools for examining a set of images that detail gene expression in the mouse brain. Powerful web-based viewersfor individual images and parallel examination of related images interact with an external application for three-dimensional views. The underlying dataset, generated via high-throughput analysis of expression patterns of morethan 21 000 genes in adult mouse brains, provides three-dimensional views of gene expression patterns displayedin the context of an anatomical ontology. Facilities for filtering views, saving views of interest, annotating imagesand sharing views via email support the ongoing process of analysis and provide a model for the future of integratedtools for analysing large image data sets.

IntroductionAn exceptional website must be built on the twinfoundations of great content and great tools. Greatcontent is information that extends our abilities totackle problems, answer questions and build under-standing in ways that are not otherwise possible.Powerful tools allow for the exploration of these datathrough searching, browsing and comparing itemsin a facile and comprehensive manner. Tools that aredesigned to support the tasks and goals of the endusers, rather than the data models and software struc-tures of the developers, are particularly powerful inthis regard. These tools need not be flashy – manysuccessful websites have simple interfaces – but theymust help users meet their goals.

Websites for databases of scientific images are par-ticularly challenging in this regard. Unlike sites forgenomic databases which often allow browsing, com-parison and searching in a relatively compact and

1To whom correspondence should be addressed ([email protected]).Key words: Allen Brain Atlas, data set, gene-expression profile, mouse brain,three-dimensional image, website.Abbreviations used: ABA, Allen Brain Atlas; 3D, three-dimensional; ISH,in situ hybridization.

well-defined manner, image databases must contendwith greater challenges in data presentation andquery processing. Image thumbnails are not usefulbelow a certain size, and searching often relies uponannotations which present challenges of curation andinterpretation. Many of the tasks involved in imageanalysis and comparison are much less well-definedthan they are for genomic analyses. Whereas modelsfor discussing the similarity between two sequences ofnucleotides are well-defined and understood, it is farfrom straightforward to unambiguously define howtwo images of fluorescent cells are ‘similar’. To over-come these difficulties, image database websites mustprovide both well-categorized and analysed data, andpowerful tools that help scientists use the imagesand related metadata to support their inquiries.

The Allen Brain Atlas (ABA) is a model of whatcan be achieved when well-designed tools meet a trulycompelling image database. A voluminous data set,the ABA contains in situ hybridization (ISH) imagesfrom the mouse brain is aligned to a common refer-ence atlas to support examination of gene-expressionpatterns throughout the brain. Tools for comparingimages from different regions of the brain or differ-ent genes, examining individual images in detail,

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H. Hochheiser and J. Yanowitz

Figure 1 Searching the ABAAn anatomic search for genes that are highly expressed in both the medulla and the cerebellum leads to 43 results. One image

set, for the RIKEN 2900002G04 gene, has been added to the previously selected F11r-coronal image set (see ‘Your Selections’

on the left-hand side). Available image sets for the ELOVL family member 6 are shown, along with links to external databases.

and exploring (via an external application) three-dimensional (3D) views of gene expression in thebrain from any viewpoint, work together to supportimage analysis and investigation in a manner that canboth support researchers and engage non-scientists.

DataThe ABA website is an entry point into a world ofdata. In an effort to understand gene expression inthe mouse brain at a cellular level, the Allen Insti-tute for Brain Science (Seattle, WA, U.S.A.) de-veloped a process for high-throughput capture andanalysis of ISH data from mouse brain sections. Thisexercise in ‘industrialized neuroscience’ (Markram,2007) involved an assembly-line process of data cap-ture, analysis and quality control (Allen Brain Atlas,2006a), which ultimately utilized 1 million brainsections to obtain image data on over 21 000 genes(Markram, 2007).

The intriguing picture provided by these imagesis only the beginning. Appropriate interpretation ofthese gene-expression profiles requires contextual in-formation that can be used to link gene expressionto specific areas in the brain. The Allen ReferenceAtlas is a companion set of brain section images, an-notated according to a hierarchical ontology of brainregions (Allen Brain Atlas, 2006b). Each ISH imageis associated with the closest appropriate annotatedimage from the reference Atlas, providing a roadmapthat can be used to identify brain structures in whichthe associated gene is over- or under-expressed. Thesedata can be used to compare and contrast variousgenes and sections of the brain in ways that wouldnot otherwise be possible.

A recent study from the Allen Brain Institute forBrain Science identified several interesting patternsregarding specificity of genes in various regions andgenes specific to various cell types (Lein et al., 2007).

404 C© The Authors Journal compilation C© 2007 Portland Press Ltd

Exploring mouse brain images in the Allen Brain Atlas Scientiae forum

Figure 2 Thumbnail viewerThumbnail images from an image set are shown, with one image in a heat-map expression view.

The comprehensive nature of the data set and the ana-lyses makes the ABA an impressive accomplishment.The powerful and well-thought-out tools that can beused to access the data take the ABA to a higher level,making it an invaluable resource.

Searching for image setsA session with the ABA starts with a search for rel-evant image sets. Three complementary mechanismsare provided: gene search, anatomic search and fine-structure annotation search. Textual queries in theABA query language can also be used, via an addi-tional search option.

Searches result in a list of image sets that can beselected for further analysis. These sets are groupedby gene; clicking on an entry expands the entry forthat gene to reveal the image sets available. Geneentries also contain links for both retrieving specific

details about the gene and accessing a host of externalgenomic resources.

Image sets of interest can be selected for comparisonby clicking ‘add’ in the appropriate entry (Figure 1).Up to three active sets can be selected at any time forsubsequent analysis via the thumbnail viewer or themultiple image viewer.

The thumbnail view (Figure 2) displays all of theimages from the selected series in a two-dimensionalgrid of images. Each image is labelled with uniqueidentifiers and position indicators, and links supportswitching between ISH images and an ‘expressionview’, which maps the greyscale expression data fromthe ISH images to a ‘discrete level false colour heat-map’ (Allen Brain Institute, 2006a). Double-clickingon an individual image brings up the ABA singleimage viewer for detailed exploration, or the ‘viewdetailed images’ button (also available on the searchpage) can be used to explore and compare image sets.



Figure 3 Single image viewer, with a figure from the Allen Reference AtlasThe drawing tool has been used to highlight a region of interest in red.

Single image viewerThe single image viewer shows a specific image in itsown window. Zoom and pan controls can be used tospecify image regions of interest, with an overviewwindow (in the upper left-hand corner) indicatingthe position of the zoomed region in the contextof the overall image. Three modes are possible: ISH,heat-map expression view and the annotated referenceatlas view. Drawing tools can be used to annotate theimage. Annotated images can be saved via screencapture or exchanged via email. Other images in thesame series can be accessed via a pull-down menu atthe top of the viewer window (Figure 3).

Multiple image viewerThe multiple image viewer allows for direct com-parison of images from up to three different series,alongside an appropriate view from the reference at-las. Images can be independently zoomed, panned andshown in either gene expression or heat-map view. A‘filmstrip’ at the top of the screen shows all of theimages from the currently selected series in sequence,an overview indicating the position of the currentlydisplayed image within the brain, and forward, re-verse and play ‘VCR controls’ supporting navigationthrough the image set (Figure 4). Individual imagescan also be increased in size, and ISH images can



Figure 4 Multiple image viewerComparative analysis of the heat-shock proteins HSP110, HSP30 (Selk), and HSC70T (Hspa1) are shown, with a corresponding

Allen Reference Atlas image on the upper left-hand side. The filmstrip at the top can be used to move through the various images

in the selected set (indicated at the top left-hand side). Images can be scaled and panned, or switched to gene expression

view independently. Regions of co-localization of these heat-shock proteins could help to identify cells or structures that are

particularly prone to dysfunction in neurodegenerative disorders.

be displayed alongside gene-expression views. Thesefacilities for comparing and contrasting multiple re-lated views can be extremely helpful in interpretingthese complex data sets.

The inherent variation in sample collection makesome direct comparisons particularly challenging.For example, differences in the number of brain slicesused for different genes may cause difficulties inaligning images to anatomical features. The navig-ation tools in the multiple image viewer provide theuser with controls that can help overcome some ofthese difficulties.

Additional support for comparison is provided byoverlay facilities. Images can be adjusted to use differ-

ing hues and opacity levels, and then superimposed,providing a multiple-colour overlay that allows visu-alization of multiple expression profiles simultan-eously.

Brain ExplorerAlthough not technically part of the ABA website,the companion Brain Explorer software tool providesa 3D view of gene expression in the brain, withflexibility and responsiveness that would be difficultto provide in a strictly web-based application.

Brain Explorer can be started as a stand-alone ap-plication or it can be accessed by clicking the ‘3D



Figure 5 Brain ExplorerGene expression locations for the heat-shock protein HSP30 (Selk) and HSC70T (Hspa1) genes are shown, along with orthogonal

sections and transparent outlines of various brain structures (as indicated in the hierarchy on the right-hand side).

File’ link on the image entry in the ABA search res-ults. Opening the brain atlas with a data set cor-responding to a given image series will show thelocations in the brain where that gene is expressed.A hierarchical browser of the brain atlas taxonomycan be used to select and deselect regions of thebrain to be displayed transparently, providing a con-text that can be used to interpret localization de-tails. The identity of a structure, along with its posi-tion in the taxonomy, can be retrieved with a mouseclick.

Additional context can be provided by display ofsagittal, coronal and horizontal sections, which canbe manipulated to any desired position. Full zoom,

pan and rotation controls are provided, along witha filter for limiting the display to desired expressionlevels or numbers of positions. Additional genes canbe accessed via search tools similar to those providedon the website, with colour-coding distinguishingdifferent genes (Figure 5). Bookmarks support navig-ation by providing one-click access to several impor-tant viewing perspectives. Reference atlas views thatcorrespond to various sections can be displayed, withone-click access to the single image viewer on theweb site.

Brain Explorer provides a fascinating 3D view intothe dynamics of gene expression in the brain. As thenavigation and interpretation of complex 3D images



is always a challenge for desktop computers, BrainExplorer is likely to be most powerful as a comple-mentary tool, working alongside the facilities in thesingle and multiple image viewers.

SummaryNumerous websites for imaging datasets have beencreated in recent years, including those focusing onmice (Burger et al., 2002; Magdaleno et al., 2006) andneuroscience data (Martone et al., 2004). The ABAcombines an impressive accomplishment in data col-lection and analysis with informatics tools that raisethe bar for this class of tools. The support for compar-ative analysis adds value exactly where it is needed.More importantly, rapid access to this voluminousdata set makes exploration and browsing enjoyable;one can easily imagine a modified version of this toolas an essential tool for classroom instruction. Futurecombinations of these facilities with other innova-tions in human–computer interaction, such as dy-namic user-driven annotation, have the potential tosubstantially increase our ability to gain insight fromlarge image collections.

AcknowledgementsAll Figures are screenshots taken from the ABA web-site (http://www.brain-map.org) and the Brain Ex-plorer software.

ReferencesAllen Brain Atlas (2006a) Informatics data processing.

http://www.brain-map.org/pdf/InformaticsDataProcessing.pdfAllen Brain Atlas (2006b) Allen reference atlases.

http://www.brain-map.org/pdf/Allen Reference Atlases.pdfBurger, A., Baldock, R., Yang, Y., Waterhouse, A., Houghton, D.,

Burton, N. and Davidson, D. (2002) The Edinburgh Mouse Atlasand Gene-Expression Database: a spatio-temporal database forbiological research. 14th International Conference on Scientificand Statistical Database Management (SSDBM′02)

Lein, E.S., Hawrylycz, M.J., Ao, N., Ayres, M., Bensinger, A.,Bernard, A., Boe, A.F., Boguski, M.S., Brockway, K.S., Byrnes, E.J.et al. (2007) Genome-wide atlas of gene expression in the adultmouse brain. Nature 445, 168–176

Magdaleno, S., Jensen, P., Brumwell, C.L., Seal, A., Lehman, K.,Asbury, A., Cheung, T., Cornelius, T., Batten, D.M., Eden, C. et al.(2006) BGEM: an in situ hybridization database of gene expressionin the embryonic and adult mouse nervous system. PLoS Biol. 4,e86

Markram, H. (2007) Bioinformatics: industrializing neuroscience.Nature 445, 160–161

Martone, M.E., Gupta, A. and Ellisman, M.H. (2004) e-Neuroscience:challenges and triumphs in integrating distributed data frommolecules to brains. Nat. Neurosci. 7, 467–472

Received 1 March 2007/4 April 2007; accepted 10 April 2007

Published on the Internet 19 June 2007, doi:10.1042/BC20070031


If I only had a brain: exploring mouse brain images in the Allen Brain Atlas

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