New Reagent Helps Map Neural Connections in Brain

An improved rabies virus tracer visualizes neural circuitry in the brain, helping to understand more about motor diseases and neurodevelopmental disorders.

Researchers at the Salk Institute for Biological Studies (La Jolla, CA, USA) have engineered an optimized glycoprotein (OG) variant of the monosynaptic rabies virus (MRV) system that improves trans-synaptic efficiency. The new approach is based on a genetic modification of the virus that allows infection to be targeted to specific types of neurons, thus allowing virus spread to be controlled. The result is that while neurons are illuminated across the entire brain, the tracer reagent illuminates only those that are directly connected to neurons of interest.

The oG variant is a codon-optimized chimeric glycoprotein that merges the transmembrane-cytoplasmic domain of the B19G rabies virus, and the extracellular domain of the Pasteur virus strain glycoprotein. The resulting oG variant increases tracing efficiency for long-distance input neurons by up to 20-fold--when compared to B19G alone--allowing more complete study of monosynaptic input neural networks in the brain. The study describing the improved technique was published on April 14, 2016, in Cell Reports.

“To truly understand brain function, we have to understand how different types of neurons are connected to each other across many distant brain areas. The rabies tracing methods we have developed made that possible, but we were only labeling a fraction of all of the connections,” said senior author Professor Edward Callaway, PhD, who developed MRV. “Such a dramatic improvement in a critical tool for neuroscience will help researchers illuminate aspects of brain disorders where connectivity and global processing goes awry, such as in autism and schizophrenia.”

“With this new rabies tracer, we can visualize connectivity neuron by neuron, and across long distance input neurons better than with previous rabies tracers,” said lead author Euiseok Kim, PhD, of the Salk systems neurobiology laboratories. “Although this improved version is much better, there are still opportunities to improve the rabies tracer further as we continue to examine other rabies strains.”

The MRV system, developed in 2007 and refined by Professor Callaway and other researchers for targeting specific cell types in 2010, uses a modified version of the rabies virus to infect a brain region. When the system is applied in genetic mouse models, researchers can see specifically how sensory, motor, and reward structures in the brain connect to medium spiny neurons (MSNs) in the basal ganglia. There are two major projection cell types in the striatum of neurons that target downstream basal ganglia and have opposing effects on motivated behavior, but the differential innervation of these neuronal subtypes is not well understood.

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Salk Institute for Biological Studies