Study: Transcription factor codes patterning neuronal groundplans of the cerebrum (DOI: 10.1038/s41586-026-10526-3)
While E. Josie Clowney would never suggest that neuroscience is simple, a new study by her team at the University of Michigan could drastically reduce complexity in future studies.
Their work focused on instinctual behaviors in fruit flies, but it has the potential to accelerate work to better understand the neurobiology that underlies behavior and decision-making in mammals, including humans.
The research establishes a new way to understand neurons, their connectivity and the behaviors they control. Within this new framework, the researchers can circumvent the conventional approach of considering each type of neuron individually and instead focus on groupings defined by shared structure and by two sets of regulatory genes.
The work was supported by the Pew Charitable Trust and the McKnight Endowment Fund for Neuroscience, with additional funding from the National Institutes of Health and U.S. National Science Foundation.
While there are more than 8,000 kinds of neurons in the fruit fly cerebrum-the part of its brain where instinctual behaviors are hardwired-there are less than 200 major structural groups, or ground plans. Led by Najia Elkahlah, who recently defended her doctoral thesis in the Clowney lab, the team's discoveries revealed how these ground plans get set up. There is a sort of order or hierarchy, where one set of genes coordinates the formation of the ground plan, and the other set produces small differences in shape and connectivity among neurons within each ground plan.
"Instead of studying all 8,000 kinds of neurons, we can instead understand how circuits work by studying these 200 modular elements that are wired together in various ways for different functions," said Clowney, associate professor in the Department of Molecular, Cellular and Developmental Biology.
These gene sets have homologues in mammals, and many of them are known to be critical in mammalian neural development. This raises the possibility of discovering similar simplifying frameworks in other organisms.
"At this moment, it's not yet possible to ask if the same rules apply to analogous parts of mammalian brains, because we don't know enough about the relationships among circuits, genes or developmental programs that operate there," Clowney said. "But I feel strongly that there will be simplifying rules of some sort in the mammal as well, and that we or others will be able to discover them if we take inspiration from the way we went about making this discovery."
The research was published in the journal Nature.
Taste and cease
Scientists have been studying the humble fruit fly as a biological model since before they knew genes were made of DNA. That history has yielded fundamental biological discoveries, as well as a substantial body of work on which to build new ones.
"The reasons we work with this animal today are because it has useful characteristics that simplify our experiments and interpretations, and because we want to take advantage of 100 years' worth of knowledge," Clowney said. "In my opinion-though others in the field might disagree-we don't study this animal because it is 'special,' but rather as a generic example of 'an animal.'"
Within the Drosophila cerebrum, researchers including Clowney had previously discovered specific neural circuits linked to specific instinctual behaviors. And this specificity helped the team discover the broader ground plans that can help simplify their quest to link molecular and cellular biology to behavior.
The researchers discovered that there are two sets of regulatory genes at work. The first set controls the basic shape of the neuron, while the second set influences finer variations and connectivity.
It's this first set that gives rise to the roughly 200 ground plans. Of these 200, there's one ground plan that's connected to sensing a taste and stopping a behavior. Within that ground plan, there's neural circuitry that detects unsavory taste information and quashes feeding behavior. Another circuit detects undesirable pheromonal tastes and blocks mating behavior. The team was able to identify the second set of genes that gave rise to these two distinct neural pathways and behaviors.
"Thinking about these two sets of genes separately allowed us to relate the developmental programs to the function of circuits," Clowney said. "We identified two sets of genes that give neurons in the decision-making center of the brain their gross versus fine characteristics, and defined a new way to study these circuits."
U-M research lab technician Joe Carter and doctoral students Yunzhi Lin and Yijie Pan also contributed to the study. The Clowney lab worked in collaboration with Troy Shirangi, a professor at Villanova University. Additional support for the project was provided by the U-M Advanced Genomics Core and the U-M Single Cell Spatial Analysis Program.
