Success in figuring out the wiring diagram of the brain could transform the field of neuroscience, with implications for learning more about disorders varying from depression and schizophrenia to Parkinson’s and Alzheimer’s disease.

Dr. Lynn Enquist, a professor in Princeton University’s (Princeton, NJ, USA) department of molecular biology and in the Princeton Neuroscience Institute, is leading the project to utilize genetically engineered viruses as ‘explorers’ that move throughout the nervous system, following the connections between neurons and reporting on their activity along the way. “Over the years, the understanding of how cells in the brain are connected has been a major problem,” stated Dr. Enquist, a professor of molecular biology. “How can this blob of tissue do everything [it does]? We’re missing a lot of information about how the brain works.”

The U.S. National Institutes of Health (NIH; Bethesda, MD, USA)-funded project hinges on the creation and use of a genetically modified virus that causes neurons to generate colorful fluorescent proteins. As the virus spreads, it leaves a colorful path through the brain in its wake. Some of the engineered viruses are designed to make the neurons glow brightly when they are active. “These DNA-based technologies allow us to put little labels on neurons that tell who they are connected to,” said team member Dr. Samuel Wang, an associate professor in the department of molecular biology and in the Princeton Neuroscience Institute.

Chemicals exist that can be used to trace brain connectivity, including specific molecules from the horseradish plant and the cholera toxin, but they become increasingly dilute as they spread throughout the brain. Other chemicals can alter color or brightness when a neuron is active, but they label all cells indiscriminately, leading to a foggy image. Because viruses replicate, they are self-amplifying and do not become less concentrated as they move away from their entry point into the brain, making them a potential tool for researchers seeking to probe the elusive areas of the brain.

Viruses also can target subsets of neurons, making them glow--and therefore stand out--in sharp relief. Dr. Enquist and his collaborators are now conducting laboratory research in test tubes and mice as they try to increase essential knowledge about neural connectivity, which has significant implications for understanding the human brain.

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