“When we measured the genes in our samples,” says Lein, “what we actually saw was the average output of all the cells in that sample.” When they were through, Lein and his colleagues had mapped the location and activity of some 20,000 genes in anatomical regions throughout the brain. But they still didn’t know which individual cells those genes came from.
UCSF’s new brain atlas doesn’t span as many regions as the Allen Institute’s (not yet, at least), but what anatomical areas it does covers it does with much greater specificity. “The difference between previous studies and ours is the difference between a smoothie and a fruit salad,” says study coauthor Alex Pollen. “They have the same ingredients, but one mixes them together and the other looks at them individually.”
The UCSF researchers focused on regions of the developing brain that eventually become the basal ganglia, which helps orchestrate things like voluntary motor control, and the cerebral cortex, the largest region of the mammalian brain and the seat of many human cognitive abilities. By examining the expression of individual cells from 48 brains at various stages of development, the researchers were able to trace a handful of genetic and developmental patterns to 11 broad categories of cell—and make a number of unexpected observations.
“One big surprise is that region-specific neurons seem to form very early in the developmental process,” says neurobiologist Tomasz Nowakowski, who led the study. That includes neurons in the prefrontal cortex, whose formation neuroscientists have long theorized to be influenced by sensory experience. But the new atlas suggests those areas begin to take shape before sensory experiences even have a chance to take place. That’s the kind of finding that could fundamentally alter neuroscientists’ understanding of the structure and function of adult brains.
The project’s other takeaways are too numerous to list here. But that’s the thing about brain atlases: They’re great at generating questions. “These things are foundational,” Lein says. “The reason these atlases are valuable is you can do a systematic analysis in one fell swoop and generate 10,000 hypotheses.” Testing the hypotheses generated from this latest atlas will hinge on researchers’ ability to access and add to it, which is why Nowakowski and his colleagues collaborated with UC Santa Cruz computer programmer Jim Kent to visualize their database in an interactive, online visualization.