Hobert lab paper published in Nature

Brittany Bistis
December 17, 2021

A new paper from the lab of Dr. Oliver Hobert, published in the December 2 issue of Nature, offers fresh insight into the links between genes, the brain, and behavior. 

The paper addresses a fundamental problem in genetics and neuroscience: How do molecular changes in genetic pathways cause large-scale changes in an animal over the course of its development? In mammals, the central nervous system undergoes massive structural and physiological changes from the time the animal is born to adulthood. This development can be modeled on a small scale by changes in the expression of genes enriched in the brain over time or on a large scale by the behavioral changes the animal exhibits as it grows into an adult. The challenge remains causally linking changes in genetic pathways at the molecular level with anatomical and behavioral changes in the whole animal. 

Using the worm C. elegans, Dr. Haosheng Sun, a postdoc in the Hobert lab, characterized both the transcriptome—the complete set of all RNA transcripts in the animal—and the motion behavior for every major timepoint in worm development from hatching to adult. As reported in the December 2nd issue of Nature, Dr. Sun found a comprehensive list of differentially expressed genes in the nervous system during development. By comparing and clustering gene expression trajectories, researchers accurately constructed a unique transcriptomic profile for each developmental timepoint. And by using a high-resolution worm motion tracking system, they were able to associate each developmental timepoint with specific behavioral motion. This led to identifying how the expression of specific genes is linked to behavioral changes in the developing worm.

For example, after hatching, worms in the larval stage like to explore their surroundings. As the larvae mature, their exploratory behavior decreases, and they prefer to dwell in one place. The Hobert lab discovered that this change in behavior can be linked to a specific neuropeptide: neuropeptide nlp-45 is required for maturing worms to make the shift from explorers to dwellers. Knockout, rescue, and ectopic expression experiments showed that the increased and more pervasive expression of the gene encoding nlp-45 at later worm developmental stages is a causative factor in older worms' decreased desire to explore and increased interest in dwelling in one place. This temporal expression of nlp-45 precipitates behavioral developmental milestones as the worm matures. 

Combining transcriptomic profiling and motion tracking data, the Hobert lab has presented a comprehensive view of the genetic and functional changes in each stage of worm development from hatching to adulthood, correlating gene expression and whole organism behavior. Using classical genetics approaches, the lab further found how one gene is responsible for a specific animal behavior. The discovery of causal links between gene expression and behavior provides a deeper and mechanistic understanding of what drives animal behavior on the molecular level.