Automating Brain Mapping

RESEARCH HIGHLIGHTS NEUROSCIENCE Automating brain mapping Two new platforms allow single neurons to be imaged throughout the mouse brain. Large-scale neuroscience projects such as the BRAIN Initiative seek, among other goals, to map the projections of individual neurons throughout the whole brain. Current techniques for this rely on either bulk labeling of bundles of axons or sparse labeling in combination with serial tissue sectioning and manual tracing of axons Fluorescently labeled neurons and their between sections. The former approach is projections (green) and surrounding nuclei relatively easy to carry out but lacks suffi- (purple) in the mouse cortex. Adapted with permission from Gong et al. (2016). cient resolution to identify the projections of individual neurons, whereas the latter approach allows for single-cell resolution and Eugene Myers of the Janelia Research but is exceedingly time-consuming. Two Campus, along with their colleagues, recent- new studies describe methods for automat- ly described a platform for automated imaged whole-brain single-cell tracing that over- ing and reconstruction of individual neurons come many of these limitations. throughout the brain (Economo et al., 2016). In one paper, Qingming Luo of Huazhong Similar to the work of Luo and colleagues, University of Science and Technology and this automated platform alternately images colleagues describe a high-throughput and sections tissue; however, the system method for whole-brain fluorescent imaging uses two-photon laser scanning microscopy (Gong et al., 2016). The method builds upon rather than SIM. In addition, the research- previously developed platforms in which a ers incorporated a step in which the whole resin-embedded brain goes through auto- brain is optically cleared, facilitating tracing mated cycles of imaging with a microscope of fluorescently labeled axons. and sectioning with a vibratome to expose a The authors also developed a computa- Nature America, Inc. All rights reserved. America, Inc. Nature new, un-imaged tissue surface. The authors tional platform for automatic image regis- 6 improved upon previous iterations of the tration and axon tracing, which should save © 201 method by using structured illumination researchers a lot of time and tedium. The microscopy (SIM), which allows for much authors provide extensive validation of this faster data acquisition than other types of automated process, showing that it is able to microscopy. In the past, the trade-off for follow individual axons far from their neu- npg this speed has been lower resolution, but ronal cell bodies, with low error rates even simple adjustments made by the researchers when labeled axons cross over each other. allowed them to increase the resolution to These new methods promise to facili- around that of confocal microscopy. tate the mapping of neuronal projections The new method also implements real- throughout the mouse brain, and the time staining of cell nuclei just prior to each improvements in speed move researchers imaging cycle. The nuclear staining reveals closer to being able to map projections in known cytoarchitectonic landmarks in the the brains of larger animals. Maps generated brain, such that fluorescently labeled neu- using these techniques will undoubtedly be a rons can be localized to particular regions, valuable resource for the neuroscience com- making the process of axon tracing much munity as it seeks to better understand the easier and more accurate. The authors way the brain is wired, and how this wiring demonstrated the utility of their technique leads to function. in tracing individual neurons in multiple Brigitta B. Gundersen regions of the mouse brain. RESEARCH PAPERS The work of labeling neurons and of sec- Gong, H. et al. High-throughput dual-color tioning and imaging tissue is only one bar- precision imaging for brain-wide connectome with rier to mapping axon projections. Manually cytoarchitectonic landmarks at the cellular level. Nat. Commun. 7, 12142 (2016). tracking a labeled axon between serial Economo, M.E. et al. A platform for brain-wide sections can be even more difficult and imaging and reconstruction of individual neurons. time-consuming. Jayaram Chandrashekar Elife 5, e10566 (2016). NATURE METHODS | VOL.13 NO.9 | SEPTEMBER 2016 | 719.

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