Engineered Rabies Virus Illuminates Neural Circuitry

Originally published by Hannah Thomasy, PhD, for the Scientist on June 14, 2024

Scientists turned a deadly virus into a crucial tool for understanding the wiring of the brain.

 

Rabies labeling helps scientists identify neurons in the primary visual cortex that connect to two different higher visual brain regions. Marina Garrett 

In 1906, pathologist Camillo Golgi and neuroscientist Santiago Ramón y Cajal won the Nobel Prize for their work on the structure of the nervous system. More than a century later, the puzzle of nervous system organization—the intricately tangled mess that results from each neuron’s connections to thousands of others—remains incomplete.

Yet, fully developing scientific understanding of these connections is crucial, said Edward Callaway, a systems neurobiologist at the Salk Institute. “If you don’t have some knowledge about how the different parts are interacting, there’s no way to generate a hypothesis about how they’re working together.” 


Neuroscientist Edward Callaway uses monosynaptic rabies virus tracing to map neuronal circuits in the cortex..Credit:Chris Keeney

Disentangling this complex network to create an orderly map of neuronal connections is a problem that researchers have been working on for decades. In the 1980s, researchers began searching for a marker that could function as a transneuronal tracer. They needed something that could hop across synapses, spreading from neuron to neuron efficiently enough to reach detectable levels even in cells connected across long distances. Luckily for the scientists (although perhaps unluckily for humanity in general), a handful of neuron-specializing viruses have evolved to do exactly that. 

Thanks to the work of pioneering virologists, neuroscientist Gabriella Ugolini, now at the Paris-Saclay Institute of Neuroscience, knew that herpes simplex virus 1 (HSV-1) preferentially infected neurons, and that it could spread across synaptic connections. Unlike a dye or a toxin, a virus would not need to cross synapses in large amounts because it could replicate to detectable levels using the host’s cellular machinery. In the late 1980s, she demonstrated that when injected into a peripheral nerve, HSV-1 spread across synapses to neurons in the brain.1 The virus-infected neurons could then be easily identified in sections of brain tissue using immunohistochemistry, providing a clear picture of the chains of connection.

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