commentary

Scientific priorities for the Initiative Aravi Samuel, Herbert Levine & Krastan B Blagoev

We present a summary of the scientific deliberations and major conclusions that arose from a workshop on the BRAIN Initiative.

In his State of the Union address on best strategies are for performing large- Current technologies are starting to make it 21 January 2013 and in a press conference on scale neural recording as well as the syn- possible to record from most of the neurons 2 April 2013, US President Barack Obama ergistic research activities that will enable in the small brain of the larva7, but called for a national program to develop the activity patterns to be analyzed and substantial technical breakthroughs will be technologies to accelerate our understand- properly understood. To help address these required to record all of the neural activity ing of how the brain works. One aspect of issues, the NSF and the Kavli Foundation in an animal as large as a mouse. this new initiative would be the mapping cosponsored a 2-day workshop in early There was a consensus that brain activity of neural firing patterns in behaving ani- May in Arlington, Virginia, USA, drawing maps are indeed crucially important, and mals, which would show how brain activity more than 100 leading scientists (http:// that we therefore need to invest heavily in underlies mental activities and behaviors. physicsoflivingsystems.org/brainstructure- technology that would enable us to record This plan—initially called the Brain Activity andfunction/). The goal was for the par- from many more neurons than we can Map—was developed in a series of meetings ticipants to discuss their own views about currently. Electrical probes must be made and workshops cosponsored by the Kavli what the major obstacles to understanding smaller and more durable, and we need Foundation, Gatsby Foundation and Allen the brain are and to present their hopes to develop less invasive devices that allow Brain Institute, culminating in several pub- for the BRAIN Initiative. The meeting was longer recording with higher spatial and lished reports1–3. Once the White House live streamed to the general public to pro- temporal resolution with minimal disrup- signaled interest, the effort, now called the mote transparent debate. Members of the tion. We must also invest heavily in opti- BRAIN (Brain Research through Advances Working Group of the Advisory Committee cal neurophysiology to generate more and

© 2013 Nature America, Inc. All rights reserved. America, Inc. © 2013 Nature in Innovative Neurotechnologies) Initiative, to the NIH for the BRAIN Initiative (http:// better genetically encoded probes, both for rapidly became a priority for federally fund- www.nih.gov/science/brain/acd-roster. stimulating neurons and for recording calci- ed scientists4. pdf) as well as many government represen- um and voltage dynamics. In addition, bet- Of critical importance for the community tatives attended the meeting. A full report ter microscopes will be needed if they are to npg is how the major US federal agencies that of the meeting will be made available at the be used most effectively: for recording from are charged with implementing the BRAIN workshop website at a later date; here we— as many neurons as possible, for as long as Initiative—the National Science Foundation representing one of the meeting sponsors possible and with high temporal resolution (NSF), National Institutes of Health (NIH) and two of the organizers—provide a short to resolve circuit computations. and Defense Advanced Research Projects summary of the scientific deliberations and However, if the quest is to understand the Agency (DARPA)—will translate the loosely the major conclusions. brain, then just creating large-scale maps defined mandate to understand the human As mentioned above, one major focus of of brain activity is not going to be enough. brain and its disorders into specific scientific the BRAIN Initiative is to develop technol- First, to deal with the enormous amount of priorities and projects. As we discuss below, ogy for recording from many neurons and data that come from massive recordings, major questions remain regarding what the manipulating their activities in behaving sophisticated methods will be needed to animals. Advances in the last decade have store, access, distribute and analyze that made it possible to measure neural activities data. A strong cyber infrastructure will Aravi Samuel is in the Department of Physics and Center for Brain Science, , in large ensembles of neurons, as many as be essential to the success of laboratories, Cambridge, Massachusetts, USA, and hundreds of neurons at once in the brain of departments and research universities: this Herbert Levine is in the Department of a mouse5 or across the retina of a primate6. can be built on experience from other ‘big Bioengineering, Rice University, Houston, Texas, The view that emerged from prior meetings data’ fields of science such as genomics or USA. Krastan B. Blagoev is at the US National Science Foundation, Arlington, Virginia; in the Department that crafted the BRAIN Initiative is that we high-energy physics. Bringing experts from of Radiology, Massachusetts General Hospital and cannot hope to understand the brain with- these fields into will be inte- Harvard Medical School, Boston, Massachusetts; out being able to record from a substantial gral to the BRAIN Initiative. and at the Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, USA. fraction of its neurons; the exact size of that More critically, brain activity maps need e-mail: [email protected] fraction is a subject of vigorous debate. to be augmented by other data and by an

nature methods | VOL.10 NO.8 | AUGUST 2013 | 713 commentary

analysis framework informed by theory. studies of small animals such as worms, Hughes Medical Institute’s Janelia Farm Important information is contained in the flies, fish and mice. Machine learning Research Campus, that have been able to structure and wiring of the neural circuits approaches have been successful in reduc- contribute powerful and widely used tools that are being recorded from. Having in ing multidimensional behavioral dynam- and data sets. hand the connectivity of the wiring dia- ics to specific behavioral rules that might In summary, the workshop called for a gram will allow researchers not merely to be instantiated in brain circuits. For want broad interpretation of the major chal- find correlations in the activity in distant of a better word, full ‘behavior-omes’ that lenges to neuroscience. Recording from as neurons but also to understand the mecha- describe time-varying behavior of animals many neurons as possible in whole nistic basis of such correlations as arising in defined environments would provide should be viewed as one necessary part of in the flow of information through neural large data sets across which to analyze con- a multipronged approach that combines wiring and across synapses. Reconstruction nectomes and activity maps, thereby link- quantitative behavioral analysis of whole of connectivity patterns across whole brains ing behavior to the structure and function animals, synapse-level studies and func- (‘’ that are detailed enough to of underlying circuits. tional analysis with single-cell resolution specify every synapse between every pair of In recent years, the technology that is across whole brains. Each of these parts has cells) would provide the structural frame- needed to understand the brain has been technological needs, data handling require- work for helping interpret neural dynam- rapidly advancing. However, the technolo- ments and informative theoretical under- ics. Efforts in dealing with vast data sets of gies for mapping brain activity, behavior pinnings. The different traditions of the structural information will also benefit from and structure must be brought together to NSF, NIH and DARPA may be extremely an investment in cyber infrastructure. answer the most fundamental questions. valuable in promoting synergistic progress For many years, it has been possible to Most of these extraordinary tools will not in these disparate areas. To quote President record from all the neurons in the stoma- be available to most researchers because Obama at the end of his White House togastric ganglion of the lobster8 or from they are expensive or require too much address, “Let’s get to work.” all the neurons in a region of the retina9. expertise for small individual labs to read- ACKNOWLEDGMENTS And yet it cannot be said that these sys- ily learn and use. Thus, beyond making We thank J. Lichtman, J. Sanes and E. Marder for tems are solved and that the principles of lists of important scientific questions and their careful reading of this report. information processing are fully under- methods (that are easily agreed upon to be COMPETING FINANCIAL INTERESTS stood. Thus, another emerging consensus important), the neuroscience community The authors declare no competing financial interests. was that advanced theoretical concepts needs to engage in an important discussion regarding how activity encodes informa- as to how to reconfigure its sociology for 1. Alivisatos, A.P. et al. ACS Nano 7, 1850–1866 (2013). tion and computation would need to be the coming era. This would include how to 2. Alivisatos, A.P. et al. Science 339, 1284–1285 developed hand in hand with the proposed share resources, how to reward collabora- (2013). advances in measurement technology. tion and how to promote multidisciplinary 3. Alivisatos, A.P. et al. Neuron 74, 970–974 (2012). Emphasis should be placed on connecting research and find proper slots for the 4. Insel, T.R., Landis, S.C. & Collins, F.S. Science general ideas (such as the brain performing researchers who will bring needed techni- 340, 687–688 (2013). 5. Buzsáki, G. Nat. Neurosci. 7, 446–451 (2004).

© 2013 Nature America, Inc. All rights reserved. America, Inc. © 2013 Nature Bayesian inference) with precise predic- cal know-how to these new activities but 6. Litke, A.M. et al. IEEE Trans. Nucl. Sci. 51, tions as to how these could be detected in who will not by themselves carry out tradi- 1434–1440 (2004). the soon-to-be-available data. tional neuroscientific studies. An impor- 7. Ahrens, M.B. et al. Nature 485, 471–477 A quantitative understanding about what tant recent development in the sociology (2012). npg the brain does requires an understanding of neuroscience has been marked by the 8. Marder, E. & Bucher, D. Annu. Rev. Physiol. 69, 291–316 (2007). of how to quantify animal behavior. Recent establishment of private laboratories, such 9. Meister, M., Pine, J. & Baylor, D.A. J. Neurosci. years have seen rapid advances in behavior as the Allen Brain Institute and Howard Methods 51, 95–106 (1994).

714 | VOL.10 NO.8 | AUGUST 2013 | nature methods Copyright of Nature Methods is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.