One focus of our work is on engineering systems for identifying and manipulating neurons that are directly synaptically connected either to a targeted single neuron or to a genetically-defined neuronal population of interest. The first system for such “monosynaptic tracing” was invented by Ian and colleagues at the Salk Institute in 2007 and has become a widely used technique in neuroscience, remaining the best (or even only) way of identifying cells directly connected to a targeted neuronal group without prior information. The original system, based on rabies virus, is not without its drawbacks, however, and we are currently improving it dramatically. In one arm of the work, we are developing a version of the system that is completely nontoxic to neurons: whereas the first-generation rabies virus is toxic to neurons on a timescale of ~2 weeks, a second-generation rabies virus that we have developed leaves neurons alive and completely healthy indefinitely. In a second arm of the research, we are developing systems for anterograde monosynaptic tracing: whereas the existing monosynaptic tracing system only identifies neurons directly presynaptic to a targeted neuronal population, the systems that we are developing are for identification, study, and manipulation of those neurons that are directly postsynaptic to the targeted cells. Both of these efforts should result in techniques that are transformatively useful for neuroscience.
