Highlights and Perspectives on Evolutionary

Brain Behav Evol 2014;83:1–8 Published online: February 28, 2014 DOI: 10.1159/000360152

NSF Workshop Report: Discovering General Principles of Nervous System Organization by Comparing Brain Maps across Species

a b c d Georg F. Striedter T. Grant Belgard Chun-Chun Chen Fred P. Davis e f g h i Barbara L. Finlay Onur Güntürkün Melina E. Hale Julie A. Harris Erin E. Hecht j k l m c Patrick R. Hof Hans A. Hofmann Linda Z. Holland Andrew N. Iwaniuk Erich D. Jarvis n o p q r Harvey J. Karten Paul S. Katz William B. Kristan Eduardo R. Macagno Partha P. Mitra s t u v Leonid L. Moroz Todd M. Preuss Clifton W. Ragsdale Chet C. Sherwood w f x o Charles F. Stevens Maik C. Stüttgen Tadaharu Tsumoto Walter Wilczynski a b Department of Neurobiology and Behavior, University of California Irvine, Irvine, Calif. , Semel Institute for Neuroscience and c Human Behavior, University of California Los Angeles, Los Angeles, Calif. , Department of Neurobiology, Duke University, Durham, d e N.C., Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Va. , Department of Psychology, , f g Ithaca, N.Y. , USA; Department of Psychology, Ruhr University Bochum, Bochum , Germany; Department of Organismal Biology and h i Anatomy, University of Chicago, Chicago, Ill. , Allen Institute for Brain Science, Seattle, Wash. , Department of Psychology, j State University, , Ga. , Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount k l Sinai, New York, N.Y. , Department of Cell and Molecular Biology, University of Texas at Austin, Austin, Tex. , Scripps Institution of m Oceanography, University of California San Diego, San Diego, Calif. , USA; Department of Neuroscience, University of Lethbridge, n o Lethbridge, Alta. , Canada; Department of , University of California San Diego, San Diego, Calif. , Neuroscience p q Institute, , Atlanta, Ga. , Sections of Neurobiology and Cell and Developmental Biology, Division of r Biological Sciences, University of California San Diego, San Diego, Calif. , Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. , s Department of Neuroscience and The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, Fla. , t Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, Ga., u v Department of Neurobiology, University of Chicago, Chicago, Ill. , Department of Anthropology, The George Washington University, w x Washington, D.C., The Salk Institute for Biological Studies, La Jolla, Calif. , USA; Brain Science Institute RIKEN, Wako , Japan

Abstract anatomical, and physiological data. This research will iden- Efforts to understand nervous system structure and function tify which neural features are likely to generalize across spe- have received new impetus from the federal Brain Research cies, and which are unlikely to be broadly conserved. It will through Advancing Innovative Neurotechnologies (BRAIN) also suggest causal relationships between genes, develop- Initiative. Comparative analyses can contribute to this effort ment, adult anatomy, physiology, and, ultimately, behavior. by leading to the discovery of general principles of neural These causal hypotheses can then be tested experimentally. circuit design, information processing, and gene-structure- Finally, insights from comparative research can inspire and function relationships that are not apparent from studies on single species. We here propose to extend the comparative This article is simultaneously published in the Journal of Comparative approach to nervous system ‘maps’ comprising molecular, Neurology (DOI 10.1002/cne.23568).

© 2014 John Wiley & Sons, Inc. and S. Karger AG, Basel Georg F. Striedter 0006–8977/14/0831–0001$39.50/0 Department of Neurobiology and Behavior Center for the Neurobiology of Learning and Memory, University of California Irvine E-Mail [email protected] 2205 McGaugh Hall, Irvine, CA 92697-4550 (USA) www.karger.com/bbe E-Mail georg.striedter @ gmail.com Downloaded by: 89.245.253.175 - 3/25/2014 10:12:59 AM guide technological development. To promote this research and distribution must be developed and respected. To that agenda, we recommend that teams of investigators coalesce end, it will help to form networks or consortia of researchers around specific research questions and select a set of ‘refer- and centers for science, technology, and education that fo- ence species’ to anchor their comparative analyses. These cus on organized data collection, distribution, and training. reference species should be chosen not just for practical ad- These activities could be supported, at least in part, through vantages, but also with regard for their phylogenetic posi- existing mechanisms at NSF, NIH, and other agencies. It will tion, behavioral repertoire, well-annotated genome, or other also be important to develop new integrated software and strategic reasons. We envision that the nervous systems of database systems for cross-species data analyses. Multidisci- these reference species will be mapped in more detail than plinary efforts to develop such analytical tools should be sup- those of other species. The collected data may range from ported financially. Finally, training opportunities should be the molecular to the behavioral, depending on the research created to stimulate multidisciplinary, integrative research question. To integrate across levels of analysis and across into brain structure, function, and evolution. species, standards for data collection, annotation, archiving, © 2014 S. Karger AG, Basel

Introduction The use of traditional laboratory model thors of this essay gathered for an NSF- species has been extremely successful, both sponsored workshop at the Janelia Farm A major focus of the Brain Research in neuroscience and more generally [Krebs, Research Campus of the Howard Hughes through Advancing Innovative Neurotech- 2005], but comparative neurobiology of Medical Institute on October 23–25, 2013. nologies (BRAIN) Initiative, announced by non-model species can provide critical ad- After several introductory presentations, President Obama on April 2, 2013, is to ditional insights into fundamental princi- the participants formed six small groups, produce ‘dynamic pictures of the brain that ples of nervous system organization. For each tackling a different central question show how individual brain cells and com- example, more than 100 years ago, Brod- but also thinking about overarching issues. plex circuits interact at the speed of thought’ mann [1909] compared the cerebral cortex The following day, each group presented [quoted in: BRAIN Working Group, 2013, of many different mammals and discov- their main recommendations, and then all p. 4]. The ultimate aim of this research ef- ered that, although some cortical areas participants engaged in an extensive dis- fort, as well as others like it around the contain more or less than 6 layers, a divi- cussion. Also participating were represen- world, is to understand the functioning of sion into 6 layers best captures the complex tatives from the NSF, the NIH, and the human brains. However, much of the re- pattern of similarities and differences in White House Office of Science and Tech- search will necessarily focus on nonhuman cortical lamination seen across species. nology. After lively debate, several core ar- species, in which novel technologies can be Similarly, comparisons of central pattern eas of agreement emerged. A white paper developed and applied more efficiently, generators across a wide variety of species, summarizing these debates and the emerg- and research can be conducted at more re- both invertebrate and vertebrate, revealed ing consensus, as well as statements from ductionist levels. For example, the Japanese important principles of how groups of neu- individual participants and video footage, brain mapping initiative will focus on mar- rons generate rhythmic patterns of activi- can be found at understandingthebrain. moset monkeys (Callithrix jacchus) , a spe- ty through the interaction of membrane org (see also brainsacrossphylogeny.org). cies that can be manipulated genetically properties and synaptic connectivity [Mar- The present document is a more formal re- [Sakai et al., 2009], yet has a neocortex that der and Bucher, 2001]. In both examples, port on the group discussions and recom- is more similar to human neocortex than general principles emerged from a compar- mendations. that of other common laboratory species. ative analysis of both similarities and dif- In brief, we agreed that comparative Other brain mapping projects will include ferences across species. A third instructive studies, including both broad comparisons research on species with smaller nervous illustration of the fruits of a comparative across widely divergent organisms and tar- systems, such as nematodes (Caenorhabdi- approach is the discovery that similar com- geted studies of more closely related spe- tis elegans) , fruit flies (Drosophila melano- putations involving learning and memory cies, can provide important information gaster), zebra fish (Danio rerio), and a few may be performed by very different neural about fundamental principles of nervous other species, because those nervous sys- networks even in closely related taxa, nota- system organization, including principles tems are easier to map in their entirety than bly octopus and cuttlefish [Shomrat et al., of variation and innovation. We stress that the brains of larger animals. Although the 2011; Hochner, 2013]. data should be collected to address specific various brain mapping projects will in- Given the broad benefits of the com- research questions that can be answered clude a variety of nonhuman species, the parative approach, it is important to con- uniquely through comparative analyses. major discoveries coming out of this re- template how one might best extend a Such a comparative approach would ben- search are expected to generalize across comparative perspective to brain mapping efit from identifying one or more ‘reference species to humans. initiatives. To answer this question, the au- species’ as initial targets for thorough map-

2 Brain Behav Evol 2014;83:1–8 Striedter et al. DOI: 10.1159/000360152 Downloaded by: 89.245.253.175 - 3/25/2014 10:12:59 AM ping. These reference species may be com- terning the nervous system during early in Aplysia to general proposals about the pared to one another, but may also serve as development are far more conserved across mechanisms underlying learning and anchors for comparative analyses of other, phylogeny than researchers had expected memory. Comparative studies have also closely related species. Collectively, these [Pani et al., 2012; Holland et al., 2013]. shown that human brains exhibit dendritic comparisons are expected to reveal both These discoveries of unexpected ‘deep’ specializations and molecular expression species similarities and differences, thus conservation lurking below more superfi- patterns that may be unique to our species disclosing both highly conserved features cial species differences are important be- and are likely to foster synaptic plasticity and variation. We also recommend that all cause they promote the unification of our [Somel et al., 2009; Konopka et al., 2012; data be gathered in standardized ways that knowledge about all nervous systems. In Bianchi et al., 2013]. facilitate comparative analyses. Finally, we addition, they help us predict which fea- Comparative research that focuses on encourage funding agencies to support tures are likely to exist in species not yet variation, rather than conservation, can training in comparative research and the examined. For example, features that are also lead to the discovery of general prin- development of new technologies and shared across leeches, insects, teleost fishes, ciples. Consider, for example, a behavior or methodologies for comparative data col- birds, mice, and marmosets are likely to ex- cognitive capacity that has evolved repeat- lection and analysis. In the following sec- ist in humans as well. Conversely, features edly in diverse species, and that in each in- tions, we expand on these core recommen- that are only found in some mouse strains, stance is correlated with similar neural cir- dations. but not others, are less likely to be present cuits or physiological mechanisms. Such in us. Thus, comparative research can help convergent similarities suggest general predict which neurobiological principles principles relating structure to function. can be extrapolated to humans and, thus, For example, some birds and some great Goals of the Comparative serve as a basis for therapeutic interven- apes have independently evolved a capacity Approach to Brain Mapping tions. By contrast, the model species ap- for tool use and mirror self-recognition, proach, applied in isolation, has led to rath- and both groups of species exhibit similar, Comparative neuroscience allows the er limited success in the development of though independently evolved, neural cir- evolutionary history of neural traits to be human therapies [van der Worp et al., cuits controlling those behaviors [Prior et reconstructed. By analyzing the distribu- 2010]. al., 2008; Striedter, 2013]. Similarly, the tion of those neural traits across multiple Although the discovery of unexpected neural circuits mediating vocal learning in species, whose phylogenetic relationships conservation is both fascinating and useful, songbirds and parrots bear some similarity have already been clarified, neuroscientists the analysis of species differences can also to human language circuits [Petkov and can reconstruct when the traits first be invaluable. Closest to home, careful Jarvis, 2012], even though they are most evolved, identify which species inherited comparisons between human and nonhu- likely not homologous. Such independent- the traits from a common ancestor, and es- man primate brains can show what makes ly evolved neurobehavioral similarities tablish in which lineages the traits were our human brains unique [Preuss, 2012; strongly suggest the existence of computa- modified or lost. Although such character Sherwood et al., 2012; Fjell et al., 2013; Fin- tional constraints that limit the possible phylogeny reconstructions may be amend- lay and Workman, 2013; Passingham and neural mechanisms capable of generating ed as more species are sampled and phylog- Wise, 2013], at least among primates [Pet- the respective forms of cognition. Analo- enies revised, the underlying methodology kov and Jarvis, 2012]. In addition, variation gous studies of variation in brain develop- is well established [Northcutt, 1984; Nieu- in neural traits can generate novel hypoth- ment and adult nervous system organi- wenhuys, 1994]. As brain maps become eses about the mechanisms underlying zation can reveal general principles of more detailed and cover an increasing those traits. For example, one may ask evolution and development [Finlay and number of species, it will be possible to re- whether a species difference in brain anat- Darlington, 1995; Charvet et al., 2011]. construct the history of how nervous sys- omy or physiology correlates with a species Such insights could not be gleaned without tems evolved in substantial detail [Bierman difference in gene expression, either in the comparative analyses. et al., 2009]. Such research is important, be- adult nervous system or its developmental Scaling rules have long played a major cause it transforms an otherwise chaotic precursors. Such a correlation would sug- role in our understanding of organismal pattern of neural similarities and differenc- gest a causal link between the genes and the physiology [Schmidt-Nielsen, 1984; Savage es across extant species into a historical se- anatomical or physiological features, which et al., 2007; Levy and Heald, 2012], and they quence of how those nervous systems can then be tested experimentally. Similar- are also major principles in comparative evolved. This historical context, in turn, ly, researchers may ask whether a species neurobiology. Indeed, numerous neural provides the basis for extracting general difference in some behavioral trait or cog- traits vary predictably with absolute brain principles of conservation and variation in nitive capacity correlates with specific mo- size. For example, brain region propor- neural structure and function at all levels of lecular, neuroanatomical, or neurophysio- tions, neuron numbers, and average con- analysis. For example, comparative analy- logical features. Such a comparative ap- nectivity change predictably with absolute ses have shown that some brain regions proach revealed, for example, that species brain size in diverse lineages [Striedter, and neuronal pathways are surprisingly differences in associative learning among 2005; Yopak et al., 2010]. Although the spe- conserved across all vertebrates [Karten three species of sea hares, including the cific scaling rules may vary among lineages and Shimizu, 1989; Shanahan et al., 2013] well-known Aplysia californica , correlate [Herculano-Houzel et al., 2007, 2011; Le- and, perhaps, across most animals [Farries, well with differences in neuromodulation witus et al., 2012; van der Woude et al., 2013; Strausfeld and Hirth, 2013a, b]. Sim- [Hoover et al., 2006]. This comparative 2013], the rules themselves are nonetheless ilarly, many of the genes involved in pat- finding helps to link experimental studies key components of nervous system design.

NSF Workshop Report Brain Behav Evol 2014;83:1–8 3 DOI: 10.1159/000360152 Downloaded by: 89.245.253.175 - 3/25/2014 10:12:59 AM Moreover, the malleability of evolutionary and diverse other invertebrates [Lacalli and be used to map neural activity at the meso- scaling rules itself raises an important Kelly, 2003], as well as small portions of scopic scale. The activity data must then be question: what mechanisms generate the vertebrate nervous systems [Helmstaedter correlated with the corresponding anatom- scaling rules? Increases in brain size are ac- et al., 2013], are amenable to electron-mi- ical data and behavior [Alivisatos et al., companied, at least in mammals, by in- croscopic reconstructions of all neuronal 2012; Jarvis et al., 2013]. A major challenge creases in neurogenesis duration, which processes and their synaptic connections. for the construction of neural activity maps has predictable but nonlinear consequenc- Of course, the level of detail at which a is to select appropriate conditions or be- es for the size of individual brain areas brain is mapped should be determined not haviors. In some cases, it may be best to re- [Finlay and Darlington, 1995]. However, only by practical concerns, but also by the cord ‘resting state’ activity, but defining the mechanisms that regulate neurogenesis questions that are to be addressed. For ex- this state can be problematic [Stark and duration remain largely unknown. More- ample, if the questions concern develop- Squire, 2001]. Furthermore, mapping ac- over, the functional consequences of most ment, then maps must be constructed not tivity during behavior will be more relevant neuronal scaling rules have not been thor- just for adults, but also for strategically se- to answering questions about the evolution oughly explored [Karbowski, 2007; Bakken lected embryonic and juvenile stages. of specific behaviors or cognitive capaci- and Stevens, 2012]. As comparative brain Molecular brain maps likewise come in ties. mapping flourishes, more progress on several varieties. Gene expression patterns This raises an important point: if one these fronts is expected. can be mapped in whole brains, if they are goal of the research is to understand the In summary, comparative neuroscience small, or in tissue sections, using nucleic neural bases of behavior in diverse species, is a rich discipline capable of answering a acid probes. At a more detailed level, unbi- then the behaviors of interest must be ex- broad array of questions that are critically ased gene expression profiles can be creat- amined thoroughly. Indeed, comparative important for understanding nervous sys- ed for single cells using RNA-Seq or other behavioral studies can reveal important tem design. Although it might be tempting cutting-edge techniques [Puthanveettil et general principles in their own right. It is to collect comparative data before one wor- al., 2013; Serrano-Saiz et al., 2013]. The now clear, for example, that both associa- ries about which questions those data may technology for mapping proteins across tive and non-associative forms of learning, answer, we recommend that researchers species is more limited, mainly because an- such as habituation and classical condi- identify key questions first and then select tibodies that work well in some species of- tioning, are very broadly conserved across the species whose brains they want to map ten do not work in others, but technical both vertebrate and invertebrate species in light of those questions. Of course, in the advances in imaging mass spectroscopy [Macphail, 1982; Giurfa and Sandoz, 2012; long run, emerging data sets can also be [Nicklay et al., 2013] promise to overcome Sakura and Mori, 2013]. Just as Dobzhan- mined to answer new, previously neglected those challenges and also make it possible ski [1973] once observed that ‘nothing in questions. to map the distribution of lipids and other biology makes sense except in the light of molecules for which antibodies cannot be evolution’, so others have proposed that used. Another, more general problem is ‘nothing in neuroscience makes sense ex- Constructing Comparative Brain that the molecular data must be spatially cept in the light of behavior’ [BRAIN Maps aligned and integrated with the histological Working Group, 2013]. From a compara- and circuit data. When this is done, both tive perspective, both statements are equal- Nervous system ‘maps’ may contain sets of data become more valuable. In par- ly true. multiple types of data at multiple spatial ticular, gene expression patterns can help A general challenge for all brain map- and temporal scales. They may cover entire define cortical areas, cell groups, and spe- ping initiatives is to integrate molecular, brains or smaller subsystems. Anatomical cific cell types [Jarvis et al., 2013]. Integrat- anatomical, physiological, and behavioral brain maps may be macroscopic, in the ing both molecular and anatomical data is data with one another. To facilitate this in- sense that they map major brain divisions especially helpful in developmental studies, tegration, it is important for researchers to and cell groups. Particularly important are where regions or cells must be tracked agree on a spatial coordinate system in mesoscopic maps using light microscopy across successive stages of development which the data can be represented. Devel- [Bohland et al., 2009], which focus on an [Chen et al., 2013]. Fate mapping or lineage opmental data require, in addition, a well- intermediate scale of nervous system orga- analyses will likely be needed to comple- defined staging system [Workman et al., nization, corresponding to relatively re- ment such stage-by-stage developmental 2013]. Such spatial and temporal coordi- stricted collections of specific cell types, in- analyses. nate systems have been developed for sev- cluding glia as well as neurons. Anatomical Methods for mapping neural activity eral different species, but applying them to mapping at the mesoscopic scale has two tend to vary in their spatial and temporal species that have not yet been studied thor- important components: histological maps resolutions. Functional magnetic reso- oughly can be difficult. For example, close- providing the spatial distribution of differ- nance imaging and positron emission to- ly related species may progress through ent cell types and circuit connectivity maps mography, for example, have relatively low similar developmental stages at different determined with neuroanatomical tracers, spatial and temporal resolution, but are absolute rates [Striedter and Charvet, including classical tracer substances as well useful for comparing large-scale patterns of 2008], and homologous brain areas may be as neurotropic viruses. We suspect that neural activity across primate brains [Rill- located at different spatial locations in dif- these mesoscopic maps will be most useful ing et al., 2007; Mantini et al., 2013; Wey et ferent species [Nieuwenhuys, 2009]. for most comparative analyses, at least ini- al., 2013]. Single cell recordings, using mi- Another major challenge for compara- tially. However, some species with very croelectrodes, optical imaging, or immedi- tive brain mapping projects is to perform small nervous systems, such as C. elegans ate early gene expression techniques, can quantitative comparisons. Even the appar-

4 Brain Behav Evol 2014;83:1–8 Striedter et al. DOI: 10.1159/000360152 Downloaded by: 89.245.253.175 - 3/25/2014 10:12:59 AM ently simple task of comparing the size of opmental trajectory or pattern of behav- how to weight the various criteria must be brain regions across species is fraught with ior). Ultimately, those goals can only be sat- made on a case-by-case basis. challenges, as a region’s size can be com- isfied by both a broad survey of organisms In the long run, we envision the phylo- pared in absolute terms, relative to the en- and a deep analysis of closely related spe- genetic tree of animals becoming populat- tire brain, relative to the remaining brain, cies with clearly understood differences. In ed with an ever-increasing number of spe- relative to a specific reference structure, or order to advance these goals, we recom- cies whose nervous systems have been relative to expectations based on scaling mend a strategic effort to target careful- mapped to varying extents, with especially rules. Different measures may yield differ- ly selected species from phylogenetically detailed analyses of the selected reference ent results when they are correlated against widely spaced vertebrate and invertebrate species. As those brain maps proliferate, behavioral or cognitive traits [Lefebvre, groups for thorough mapping in several ever more research questions can be ad- 2012], but researchers rarely agree on domains, especially for generating connec- dressed through ever broader or more de- which measures are best. Conducting tomes and nervous system transcriptomes. tailed comparative analyses. This vision quantitative comparisons of connectomes, These ‘reference species’ would then serve has an analogy in the history of animal ge- gene expression patterns, or neural activity two purposes: as substrates for broad com- nomics. Initially, a few key species were maps is likely to be at least as challenging parisons across all animals to identify ner- studied (worm, fly, mouse, and human). and will likely require some novel analyti- vous system fundamentals and as anchors Now many different species have been se- cal approaches [Belgard et al., 2013; Bel- for more fine-grained analyses within their quenced, with their annotations depending gard and Montiel, 2013]. This is an area particular taxon to assess the meaning of crucially on the assembly of first- and sec- where research on new computational and variation in whole brains and functional ond-generation animal genomes. We envi- bioinformatic approaches to neural data subsystems. sion a similar benefit to brain mapping re- would be invaluable. Some of the reference species will be the search in focusing initially on a few refer- These observations raise a general ques- traditional ‘model species’ of neuroscience ence species, which then provide a crucial tion: how can homologous features, rang- (notably humans, macaques, rats, mice, framework for studying a greater range of ing from cell types to behaviors, be identi- zebra fish, fruit flies, and the roundworm animal nervous systems. fied in different species? Comparative neu- C. elegans ), because they offer numerous robiologists have long debated this question practical advantages, as well as existing re- [Striedter and Northcutt, 1991], but com- search communities and large reservoirs of Specific Recommendations parative brain mapping initiatives promise existing data. For example, brain maps of to clarify at least some of these debates. For laboratory mice may serve as references for Selecting Reference Species example, similar gene expression patterns comparisons to nonmammalian brains, As noted earlier, we recommend a may help to recognize homologous cell other rodents, and other mouse species or comparative approach that addresses types or brain regions [Dugas-Ford et al., strains. Similarly, human brain maps may both conserved features and variation, 2012; Vopalensky et al., 2012; Belgard et al., serve as references for broad comparative and is anchored in a set of strategically 2013; Jarvis et al., 2013; Medina et al., analyses, as well as for fine-grained com- selected reference species. Comparisons 2013], and so might similarities in physio- parisons with chimpanzees and other apes. need not be limited to the selected refer- logical activity and functional role. It However, many reference species are ence species, but may use them as useful should be noted, however, that it is possible likely to come from outside the ranks of the bases for comparison. For example, a for similar cell types to be located in non- traditional model species. To select these brain map in one reference species may be homologous brain regions, for dissimilar other reference species, researchers may used to delineate a specific neural subsys- neural networks to perform similar func- consider various criteria. In some cases, tem, which can then be mapped selective- tions, and for homologous adult structures phylogenetic position may be paramount. ly in other species. Conversely, isolated to develop from disparate developmental For example, acorn worms or lancelets bits of data from multiple species about precursors [Striedter and Northcutt, 1991]. may be useful reference species for com- which not much is known can be com- Indeed, such instances of non-correspon- parisons that span both vertebrate and in- pared more easily to one another if they dence among different levels of organiza- vertebrate nervous systems, because of are first compared to the comprehensive tion may provide vital clues to how com- their phylogenetic position near the origin map in a strategically selected reference plex systems operate and evolve. of vertebrates [Cameron et al., 2000]. In species. Thus, reference species provide other cases, it may be more important that an anchor for comparative analyses. They the genome of the species is sequenced and serve not as models for some other spe- Selecting Reference Species well annotated, that its nervous system is cies, but as a basis for comparisons that small or relatively easy to map, that the may reveal both similarities and differ- The most basic goals of a comparative species is easy to maintain and breed, that ences. approach to brain mapping are to identify key aspects of its biology have already been broadly conserved features of nervous sys- studied in detail, that a substantial scien- Collaborative Research Teams tem structure and function, to identify vari- tific community is already using the spe- Because the task of mapping the ner- ation in those features that characterize cies in its research, or that the questions vous systems of multiple species is usually particular taxonomic groups, and then to that can be answered using the species are beyond the capabilities of single laborato- understand how variation in one domain particularly important. Although a con- ries, we recommend that researchers orga- (e.g., the expression of some gene network) sensus may emerge on the criteria for se- nize themselves, as much as possible, into relates to variation in another (e.g., a devel- lecting a reference species, decisions about collaborative teams around specific re-

NSF Workshop Report Brain Behav Evol 2014;83:1–8 5 DOI: 10.1159/000360152 Downloaded by: 89.245.253.175 - 3/25/2014 10:12:59 AM search questions and around groups of spe- lenges is to create research centers that Conclusion cies through which those questions can be have the requisite equipment and exper- answered effectively. These teams should tise. Individual researchers could utilize Our 2-day workshop to discuss the fu- collectively decide which species should be these centers to collect their data at reduced ture of comparative brain mapping pro- targeted and select the relevant reference costs and, we hope, according to the stan- duced lively debates but also more agree- species. Funding agencies may support dards of the research center and the broad- ment than one might have expected. A such efforts through awards to establish or- er community. In addition, some technolo- strong consensus formed around the view ganized research networks and consortia. gies, especially analysis software, could be that data should be collected in the pursuit In the long run, significant support should developed at a few central locations and of specific questions, not simply because come through collaborative research grants. disseminated widely to the research com- the technology for collecting the data now munity. This technical support could be exists. In addition, workshop participants Data Standardization funded by multiple agencies. resonated with the concept of a reference Collaborative research teams should species, which differs from the concept of also develop standards for data collection Data Sharing and Analysis a model species in explicitly testing for spe- and storage. For example, the data should Comparative brain mapping data cies differences and spanning phylogenetic be stored in standardized file formats so should be publicly accessible over the inter- diversity in a principled, meaningful way. that it can be analyzed with common visu- net so that they can be analyzed by scien- We discussed which species might make alization software. In addition, section tists around the world. To facilitate analy- good reference species for some types of planes and scale information should be ses, new tools will need to be developed. comparisons, but in the end we felt that standardized as much as possible. One may Most important will be tools that enable these decisions are best left to self-organiz- even want to standardize tissue processing comparisons of data from brains that are at ing groups of researchers rather than our techniques and imaging parameters, at least superficially dissimilar and harbor working group. The aim of this article is to least when large-scale multispecies com- unresolved homologies. To that end, col- promote the formation of such collabora- parisons are planned. Finally, data annota- laborations with experts in multivariate tive teams and help them on their path. tion should be performed according to statistics and phylogenetic systematics may We look forward to an ever-expanding agreed-upon procedures. We support a prove especially fruitful. Funding agencies universe of comparative neural data that bottom-up process in which investigators can support such interdisciplinary efforts will yield important and unexpected dis- working with related techniques coalesce through programs such as the NSF call for coveries. around emerging standards, but we recom- ‘Advances in Biological Informatics’. mend that these standardization efforts be coordinated with those of other groups, Cross-Training such as the International Neuroinformat- Individuals in one discipline or work- Acknowledgments ics Coordinating Facility (INCF.org). The ing on one group of organisms often lack major funding agencies or other organiza- the expertise to appreciate the work per- This workshop was supported by NSF tions may also promote data standardiza- formed in other disciplines or other spe- grant IOS-1352894. We thank James tion through data sharing plans in research cies. However, major breakthroughs in Deshler and Diane Witt at the NSF for proposals. comparative neuroscience will almost cer- providing its impetus. We also thank tainly require researchers who can cross Janelia Farm and its director, Gerald Ru- Technical Support disciplinary boundaries and integrate data bin, for generously hosting the workshop. Data collection on the envisioned scale from diverse species. Therefore, scientists Much appreciated was the help of Janine requires expensive instruments and skilled should be encouraged to organize work- Stevens at Janelia Farm and Julia Pisias at labor. Anatomical mapping at the meso- shops, courses, and meetings that bring the University of California Irvine, who scopic scale is most efficiently performed together researchers with diverse back- expertly handled the workshop logistics. with modern slide scanners, rather than grounds, ranging from evolutionary biol- Thanks also to Sara Bradley, who set up traditional microscopes. Mapping at mi- ogy and genomics to statistics and the website where other documents and croscopic scales requires even more expen- computational biology. Especially impor- videos associated with this workshop may sive equipment and considerable expertise. tant is cross-disciplinary training for grad- be found: http://understandingthebrain. One way to minimize these technical chal- uate students and postdoctoral researchers. org/.

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