New five-year grant funds study of bacteria in brain development

A $2 million grant will let UO developmental neurobiologist Judith Eisen probe the relationship between symbiotic bacteria and neural development, using zebrafish as a model organism that could shed light on disease processes in humans.

The new five-year grant from the Gordon and Betty Moore Foundation will allow Eisen to illuminate the complex interactions that take place between zebrafish and their microbiome, the community of microorganisms residing within them. The work will focus on symbionts, organisms that live in close biological association with one another.

Eisen is one of 15 investigators from around the world to receive the award as part of the Symbiosis in Aquatic Systems Initiative investigator program, which provides unrestricted support to pursue innovative, risky research that has “high potential for significant conceptual and methodological advances in the area of aquatic symbiosis.”

“The investigator awards will serve as a flagship for the Symbiosis in Aquatic Systems Initiative and are expected to push the frontier of aquatic symbiosis research by providing stable and ample support for brilliant scientists who will take risks that drive creative work,” said Sara Bender, program officer of the Symbiosis in Aquatic Systems Initiative.

Eisen’s award is the largest grant received by a UO investigator from the foundation. It comes on the heels of a recent $1.1 million award received by UO biologist Kelly Sutherland funding her research into the swimming mechanisms of gelatinous marine organisms.

“The big question that we’re interested in understanding is how information flows from microbes to the nervous system of their hosts to modulate neural development,” Eisen said. “How does that information get somehow transduced by the host and sent up to the brain? What happens to that information when it’s in the brain?”

Behind that larger question, Eisen said, are many smaller ones about the signals being sent between the brain and cellular sites where host-symbiont interactions occur, about the microbial molecular mechanisms that modulate brain development, and whether that modulation feeds back to influence microbes in the gut, which constitute the largest microbial reservoir in the body.

Increasingly, Eisen says, researchers are recognizing that symbiotic bacteria are critical components in the processes that sculpt evolution, ecology, development and physiology of animals, yet remarkably little is known about how exactly those processes play out.

“Just about every neurodevelopmental and neurodegenerative disease that we know about is now thought to have some component that starts in the gut and involves some altered microbiota,” Eisen said. “Of course we don’t know if it’s a cause or a consequence. The kind of basic questions we plan to address with funding from the Moore Foundation will help us to understand where the microbiota fit into the scheme of normal brain development. This information is also critical to understand what goes wrong in disease situations.”

By elucidating some of the processes at work, Eisen hopes to answer that and other questions. To do so, she will employ many of the tools and techniques she and other researchers at the UO helped develop.

For example, her team will mutate genes in cells they suspect have an important role in transmitting information to the brain, insert genes that make those cells glow, and then used advanced microscopy to track the effect of each mutation on the candidate cells.

“That’s a big benefit of using zebrafish,” Eisen said. “We have lots of genetic tools for disabling particular pathways that project from the gut to the brain in a variety of different ways using genetics. And during the developmental stages we study, zebrafish are nearly transparent. So we can couple genetics and microscopic imaging to test how information flows and follow it at the cellular level. These types of experiments are nearly impossible in other commonly studied organisms.”

One of the UO’s pioneering zebrafish researchers, Eisen has focused much of her work on interactions between the nervous system, immune system and host-associated microbiota. The new project builds on her research showing that the microbiota affects the development and distribution of cells in the brain and on collaborative research with biologist Karen Guillemin, who heads the UO META Center that studies host-microbe interactions.

That work emphasizes the important role played by the enteric nervous system — the nervous system in the gut — in regulating the composition of the microbial community to prevent intestinal inflammation. Additionally, it expands on research with UO biologist Phillip Washbourne showing the important role the microbiota plays in the development of social behavior in zebrafish.

Although not directly translatable to humans, Eisen’s research on zebrafish could advance understanding of disease and development in humans. By expanding what we know about aquatic symbiosis, she said, the research could also help explain what happens to the microbiota of fish whose numbers are being reduced due to climate change and other environmental factors.

“Environmental changes affecting host-associated symbionts could have devastating consequences for aquatic vertebrates, as well as for other animals with conserved underlying mechanisms, potentially including humans,” Eisen said. “Our results could inform those developing strategies to help ameliorate these problems.”

—By Lewis Taylor, University Communications