Cheng Lyu is the winner of the 2025 Eppendorf & Science Prize for Neurobiology for her work in understanding how neural circuits assemble with such remarkable precision during development. Neural circuit assembly is a daunting challenge: young neurons must form specific connections with their correct synaptic partner among billions of others. How does the developing brain achieve such exquisite precision? What happens when it fails? To explore this unknown, Cheng Lyu and her research team turned to the fruit fly Drosophila, whose olfactory system offers a simple yet elegant model; only fifty types of sensory neurons each connect one-to-one with fifty matching partner neurons. Using new genetic tools that allow neurons to be tracked through development, the researchers discovered that this complex three-dimensional wiring problem is temporarily simplified. They found that partner selection occurs first on a two-dimensional surface, then along fixed, one-dimensional trajectories. Each axon follows a genetically preprogrammed path that crosses its destined partner's dendrites, drastically narrowing the search field. Experimentally rerouting axons away from their normal paths led partner neurons to fail to connect properly, demonstrating how these spatial trajectories control matching.
Drawing on single-cell RNA sequencing and genetic screening, Lyu and her colleagues identified key surface proteins that mediate attraction and repulsion between neuron types. By manipulating combinations of just five of these proteins, they successfully rewired neurons to connect with new partners, effectively rewriting the brain's wiring diagram. This engineered rewiring altered not only neural activity but also behavior. "Our study shows that synaptic specificity in developing brains can be determined by a small set of cell surface proteins acting in combination," writes Lyu. "Tweaking just a few of these components, we were able to respecify both neural and behavioral partners, opening doors for exploring how changes in circuit wiring contribute to neurodevelopmental disorders and how similar principles may have shaped the evolution of brain circuits across species."
Finalists for the prize were Constanze Depp for her essay, "White matters arising: rethinking Alzheimer's disease through the lens of myelin," and Sara Mederos for her essay," Fear protects, until it doesn't."
