In the quest to unravel the intricate neural circuitry of the brain, a technique developed in 2019 called BARseq is emerging as a powerful tool, paving the way for better understanding and treatment of conditions like Alzheimer's, schizophrenia, and depression.

Developed by Xiaoyin Chen during his postdoctoral research at Cold Spring Harbor, BARseq, a form of in situ sequencing, identifies cells in the brain by the genes they express and traces the connecting neural pathways.

Now an assistant investigator at the Allen Brain Institute, Chen has reunited with CSHL Professor Anthony Zador to push the boundaries of BARseq's capabilities. "We want to make this easy for everybody to use, faster, more sensitive. Can we read out more information with it? With much higher scale, you can start to answer different questions," Chen explains.

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Because BARseq has high throughput and low cost compared with many other spatial techniques, it is well suited for studying the spatial organization of gene expression at cellular resolution over whole-brain structures such as the cortex, according to the team.

In a new study published in Nature, they used BARseq to map the brains of nine mice, tracing gene expression in each mouse's visual cortex. The findings were remarkable: when the mice went blind, the genes in the visual cortex started to resemble those in neighboring cortical areas, suggesting a profound rewiring of neural connections.

"The effects of losing vision were very broad," Chen notes. "The visual cortex itself changes. It becomes more similar to the areas around it. There are still a lot of questions about how development controls this patterning."

Undeterred, Chen and his team are now pushing BARseq to new heights, using the technique to investigate how neural connections are wired in developing brains and how these connections evolve over time. "Understanding how cortical areas are set up is the first step in understanding these connections," he says. "But it's not enough. We still need to discover how they progress during development. BARseq can bring us closer to that goal."