Scientists Develop a ‘GPS’ to Navigate the Brain’s Neuronal Networks

In new research published April 27, 2015 on the Nature Methods website, scientists from the Hebrew University of Jerusalem and Harvard University have announced a “Neuronal Positioning System” (NPS) that maps the circuitry of the brain, similar to how a Global Positioning System (GPS) receiver triangulates one’s location on the planet. For more than a century, neuroscientists have tried to better understand how the brain works by uncovering the structure of the brain’s neuronal circuits. These brain circuits, which perform functions such as processing information and triggering reflexes, are comprised of nervous system cells called neurons that work together to carry out a specialized function. Neurons send the messages to other neurons or to the organs they innervate via specialized wire-like processes called axons.   Just like one needs to know the exact wiring of an electrical circuit to understand how it works, it is also necessary to map the axonal wiring of the neuronal circuits in order to understand how they function. Therefore a fundamental goal of neuroscience research is to understand the structural and functional connections of the brain's circuits. While numerous scientific consortiums have advanced our understanding of neuronal organization, the available mapping techniques remain imperfect: serial electron microscope techniques are limited in the area they can map, and tracer-based techniques are limited in the detail resolution.  Now, scientists from Dr. Alex Binshtok's laboratory at the Hebrew University Faculty of Medicine and Dr. Jeff Lichtman's laboratory at Harvard University have described a method that maps the location of the axonal branches of many individual neurons simultaneously at the resolution of individual axons. Thus, by “seeing” many axons in the same preparation, it become possible to comprehend the way specific neurons in one region are wiring to other neuronal types and of other regions. This new approach provides the opportunity to learn about organizational principles of neuronal networks that would otherwise be difficult or impossible to study The work was done by Dr. Shlomo Tsuriel with help from student Sagi Gudes, under the guidance of Dr. Alex Binshtok in the Department of Medical Neurobiology in the Institute for Medical Research Israel Canada of the HU Faculty of Medicine and The Edmond and Lily Safra Center for Brain Sciences in the Hebrew University, in collaboration with Dr. Jeff Lichtman from Harvard University’s Center for Brain Science and Department of Molecular and Cellular Biology. Instead of trying to trace entire neurons all the way form the axon tips to the cell body, Dr. Shlomo Tsuriel, a postdoctoral fellow from Dr. Binshtok’s lab and the lead author of the study, labeled only the cell body, but in a way that indicates the locations of its axonal branches. To that end, he used multiple injections in overlapping regions of a target organ, with three or more different colored retrograde tracers.  At each point the tracer was injected in a high concentration and spread to the area between the injection points, such that each area in the target organ had different color combination depending on the distance from the injection site. Axons innervating this area uptake the dyes and transport them in small vesicles to the cell body, such that each vesicle have color combination that reflect the area it was taken from. A few hours after the injection, each neuronal cell body was filled with vesicles in variety of colors which reflected the colors in the areas that these neurons innervate. Thus, based on the combinations and intensities of the colors in the individual vesicles transported to the cell projection sites of the axon can be outlined.  This approach is in some ways analogous to the principle used in a global positioning system (GPS) receiver, which uses distances from 3 or more satellites to triangulate its position. For this reason this technique was called Neuronal Positioning System (NPS). The description of this method was published in Nature Methods on April 27 2015.  A quote from Alex Binshtok: The new method that we developed allows us to answer a ""big question"" in neuroscience of what are the principles of the organization of neuronal circuits. Using NPS that maps many axons in same tissue we now can study what defines the routes that the neurons will send their projections and what are their targets. We can also learn how the wiring of the neuronal circuits changes during development and in variety of pathological conditions. The answers to these questions will be the first step to comprehend how the information flows and being processed in nervous system and how changes in the neuronal organization affects neuronal function. I believe that many scientists will find the NPS approach useful to help them to answer the question of how the brain works.  Support for the research came from the Humans Frontiers Science Foundation, European Research Council (ERC) under the European Union’s Seventh Framework Programme, US National Institute of Mental Health and US National Institutes of Health.