Neuron NeuroView The Brain Activity Map Project and the Challenge of Functional Connectomics A. Paul Alivisatos,1 Miyoung Chun,2 George M. Church,3 Ralph J. Greenspan,4 Michael L. Roukes,5 and Rafael Yuste6,* 1Materials Science Division, Lawrence Berkeley National Lab and Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA 2The Kavli Foundation, Oxnard, CA 93030, USA 3Department of Genetics and Wyss Institute, Harvard Medical School, Boston, MA 02115, USA 4Kavli Institute for Brain and Mind, UCSD, La Jolla, CA 92093, USA 5Kavli Nanoscience Institute and Departments of Physics, Applied Physics, and Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA 6HHMI, Department Biological Sciences, Kavli Institute for Brain Science, Columbia University New York, NY 10027, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2012.06.006 The function of neural circuits is an emergent property that arises from the coordinated activity of large numbers of neurons. To capture this, we propose launching a large-scale, international public effort, the Brain Activity Map Project, aimed at reconstructing the full record of neural activity across complete neural circuits. This technological challenge could prove to be an invaluable step toward understanding fundamental and pathological brain processes. ‘‘The behavior of large and com- To explore these jungles, neuroscientists bles. Because of this, measuring emer- plex aggregates of elementary have traditionally relied on electrodes gent functional states, such as dynamical particles, it turns out, is not to be that sample brain activity only very attractors, could be more useful for char- understood in terms of a simple sparsely—from one to a few neurons acterizing the functional properties of a extrapolation of the properties of a within a given region. However, neural circuit than recording receptive field few particles. Instead, at each level circuits can involve millions of neurons, responses from individual cells. Indeed, of complexity entirely new proper- so it is probable that neuronal ensembles in some instances where large-scale ties appear.’’ –More Is Different, operate at a multineuronal level of organi- population monitoring of neuronal ensem- P.W. Anderson zation, one that will be invisible from single bles has been possible, emergent circuit ‘‘New directions in science are neuron recordings, just as it would be states have not been predictable from launched by new tools much more pointless to view an HDTV program by responses from individual cells. often than by new concepts. The looking just at one or a few pixels on a Emergent-level problems are not effect of a concept-driven revolu- screen. unique to neuroscience. Breakthroughs tion is to explain old things in new Neural circuit function is therefore likely in understanding complex systems in ways. The effect of a tool-driven to be emergent—that is, it could arise from other fields have come from shifting the revolution is to discover new complex interactions among constituents. focus to the emergent level. Examples things that have to be explained.’’ This hypothesis is supported by the well- include statistical mechanics, nonequi- – Imagined Worlds, Freeman Dyson documented recurrent and distributed librium thermodynamics, and many-body architecture of connections in the CNS. and quantum physics. Emergent-level Indeed, individual neurons generally form analysis has led to rich branches of Emergent Properties of Brain synaptic contacts with thousands of other science describing novel states of matter Circuits neurons. In distributed circuits, the larger involving correlated particles, such as Understanding how the brain works is the connectivity matrix, the greater the magnetism, superconductivity, superflu- arguably one of the greatest scientific redundancy within the network and the idity, quantum Hall effects, and macro- challenges of our time. Although there less important each neuron is. Despite scopic quantum coherence. In biological have been piecemeal efforts to explain these anatomical facts, neurophysio- sciences, the sequencing of genomes how different brain regions operate, no logical studies have gravitated toward and the ability to simultaneously measure general theory of brain function is univer- detailed descriptions of the stable feature genome-wide expression patterns have sally accepted. A fundamental underlying selectivity of individual neurons, a natural enabled emergent models of gene regula- limitation is our ignorance of the brain’s consequence of single-electrode record- tion, developmental control, and disease microcircuitry, the synaptic connections ings. However, given their distributed states with enhanced predictive accuracy. contained within any given brain area, connections and their plasticity, neurons We believe similar emergent-level rich- which Cajal referred to as ‘‘impenetrable are likely to be subject to continuous, ness is in store for circuit neuroscience. jungles where many investigators have dynamic rearrangements, participating at An emergent level of analysis appears to lost themselves’’ (Ramo´ n y Cajal, 1923). different times in different active ensem- us crucial for understanding brain circuits. 970 Neuron 74, June 21, 2012 ª2012 Elsevier Inc. Neuron NeuroView Figure 1. Large-Scale Calcium Imaging of Neuronal Activity (A) Living brain slice from primary visual cortex of a mouse stained with the calcium indicator fura-2 AM. More than a thousand neurons are labeled and can be imaged with a two-photon microscope. From Yuste et al. (2011). (B) The calcium concentration in the soma of a neuron (bottom) faithfully tracks the electrical firing pattern of the cell (top). From Smetters et al. (1999). (C) Reconstructed ‘‘raster plot’’ of the spontaneous spiking activity of 754 cells from a similar experiment. From Cossart et al., 2003. Likewise, the pathophysiology of mental Imaging Every Spike from Every methods for voltage imaging in vertebrate illnesses like schizophrenia and autism, Neuron circuits, however, cannot capture action which have been resistant to traditional, To achieve this vision, one clearly needs potentials at a large scale with single-cell single-cell level analyses, could poten- to develop novel technologies. To date, resolution. Novel voltage sensors with tially be transformed by their consider- it has not been possible to reconstruct better signal-to-noise, less photodam- ation as emergent-level pathologies. the full activity patterns of even a single age, and faster temporal resolution are region of the brain. While imaging tech- needed. Continued improvements are The Brain Activity Map as the nologies like fMRI or MEG can capture being made in voltage indicators, and Functional Connectome whole-brain activity patterns, these tech- particularly promising are nanoparticles, To elucidate emergent levels of neural niques lack single-cell specificity and the small inorganic compounds that have circuit function, we propose to record requisite temporal resolution to permit large absorption and highly efficient emis- every action potential from every neuron detection of neuronal firing patterns. To sion. These are robust during extended within a circuit—a task we believe is preserve single-cell information while illumination and can be very sensitive to feasible. These comprehensive measure- recording the activity of complete circuits, the external electric field. Zero-dimen- ments must be carried out over time- vigorous efforts must be launched to sional nanoparticles, i.e., quantum dots, scales on which behavioral output, or massively upscale the capabilities of could be directly used to measure voltage mental states, occur. Such recordings both imaging and nanoprobe sensing. in neurons. Other nanoparticles, such as could represent a complete functional Over the last two decades, neuro- nanodiamonds (Mochalin et al., 2012), description of a neural circuit: a Brain scientists have made transformational may provide an even higher sensitivity to Activity Map (BAM). This mapping will advances in techniques to monitor the magnetic and electric fields. In addition, transcend the ‘‘structural connectome,’’ activity of neuronal ensembles. Optical by acting as ‘‘antennas’’ for light, nano- the static anatomical map of a circuit. techniques are minimally invasive and particles can greatly enhance optical Instead, we propose the dynamical can provide great spatial and temporal signals emitted by more traditional mapping of the ‘‘functional connectome,’’ flexibility, have single-cell resolution, and voltage reporters. the patterns and sequences of neuronal can be applied to living preparations, But regardless of the method chosen firing by all neurons. Correlating this even awake behaving ones (Helmchen for imaging neuronal activity, to capture firing activity with both the connectivity et al., 2011). Calcium imaging can all spikes from all neurons, one needs of the circuit and its functional or behav- measure the multineuronal activity of to increase the number of imaged ioral output could enable the under- a circuit (Yuste and Katz, 1991)(Figure 1), neurons and extend the depth of the standing of neuronal codes and their and despite a limited time resolution, this imaged tissue. A variety of recent ad- regulation of behavior and mental states. technique can partially reconstruct firing vancements in optical hardware and This emergent level of understanding patterns of large (>1,000) populations of computational approaches