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High-resolution mapping technique uncovers underlying circuit architecture of the brain

Salk scientists Sarah Leinwand and Sreekanth Chalasani

The microscope image shows nerve cells in the mouse brain that have been labeled with a modified rabies virus. These cells send direct connections to striatum, a region of the brain that regulates voluntary movement. The striatum is disrupted in degenerative disorders such as Parkinson's disease and Huntington's disease.

Photo courtesy of Nicholas Wall.

Neuroscientists have long sought to map individual neuronal connections to see how they influence specific brain functions, but traditional techniques have proven unsuccessful. Using an innovative brain-tracing technique, a team led by Edward Callaway and Gladstone Institute investigator Anatol Kreitzer has found a way to untangle these networks. Their findings, reported in Neuron, offer new insight into how specific brain regions interconnect, while also providing clues to what may happen, neuron by neuron, when these connections are disrupted.

The researchers used a sophisticated tracing technique, pioneered by Callaway and known as the monosynaptic rabies virus system, to assemble brain-wide maps of neurons that c onnect with the basal ganglia, a region of the brain involved in movement and decision- making. The system uses a modified version of the rabies virus to "infect" a brain region, which in turn targets neurons connected to it. In their study, the investigators activated the tracer genetically, ensuring that it only turned on in specific neurons in the basal ganglia. This huge technological advance enabled them to follow just the networks that connect to particular kinds of cells in the basal ganglia from other parts of the brain.

Last year, Kreitzer and his team published research that revealed clues to the relationship between two types of neurons found in the basal ganglia, which act as opposing forces, with one initiating movement and the other inhibiting it. These neurons are also involved in decisionmaking, and dysfunctions in them are associated with addictive and depressive behaviors. The findings provided a link between the physical neuronal degeneration seen in movement disorders, such as Parkinson's disease, and some of the condition's behavioral aspects. But the study left unanswered questions about how other brain regions influence the function of these neuron types.

When the monosynaptic rabies virus system was applied in mouse models, the team could see specifically how sensory, motor and reward structures in the brain connected to the two neuron types. The results will help decode how this network guides the vast array of distinct brain functions, as well as how dysfunctions in different parts of this network can lead to different neurological conditions, eventually also suggesting solutions.