If the saying "food for thought" carries weight, it's meaning — "anything that provides mental stimulus for thinking" — may prove to be scientifically prophetic by the end of an ambitious project by University of Oregon biologists.
A four-member team has just launched a federally funded project that uses zebrafish to see if microorganisms in the gut influence brain development and behavior. Their theory is that something goes wrong with certain microbes that live in the digestive system, which in turn causes problems with genes that control development of the central nervous system.
Ultimately, those genetic errors may play a role in later-in-life conditions such as autism, mental retardation, Parkinson's disease and schizophrenia.
"We are not looking at mental health, per se, but our idea is to use the zebrafish model to look at genes that are known to be involved in synapse formation and where mutations in those genes are known to be involved with autism," said Judith Eisen, a co-leader with Philip Washbourne.
Their ideas, initially submitted in separate proposals, caught the attention of the National Institute of Mental Health. After talking with NIMH officials, they combined their applications and were awarded the first of an anticipated two grants under the umbrella of the National Institutes of Health's Human Microbiome Project.
The initial grant provides $330,00 over two years to begin the project, a step that includes identifying target cells in the brain and developing a line of germ-free zebrafish for testing the effects of introduced abnormal microbes. The second grant would provide $1.3 million over three years.
"This funding allows us to look at the potential ways that the microbiota can regulate development of brain function in a way that could be very directly related to human health," said Eisen, a pioneer in the UO's development of the zebrafish model now used widely around the world. "It will allow us to look at this idea in a broad sense and then to drill down and actually learn about molecular mechanisms that are involved and which ultimately, one hopes, could translate into therapeutic approaches."
Collaborators are UO biology professors Karen Guillemin and Cristopher Niell. Each of the four scientists brings unique perspectives to the work.
Guillemin directs the National Institute of Health-funded META Center for Systems Biology at the UO. She uses zebrafish to study microbiota of the gut. Niell studies neural structure and function and has worked with zebrafish to image the formation of brain cells and to measure neural activity in response to visual cues.
Under a 2010 Guggenheim fellowship, Eisen spent a year helping design a new technique using zebrafish to study the role of resident microbes in nervous system development and function. She spent most of her time in Guillemin's lab, as well as working with biologist Joseph Fetcho at Cornell University.
Existing research suggests connections between microbes in the gut and genes involved in the formation of brain cells tied to behavior that appears later in life, Eisen noted. This information helps guide their research, said Washbourne, whose current work focuses on molecules involved in synapse development. Many of the genes he studies are affected in autism.
Synapses are the junctions between brain cells that allow signals to pass from cell to cell. This communication is essential to brain function.
"It is estimated that about 50 percent of the contribution to neuro-developmental disorders, such as autism, comes from inherited genes, while the other 50 percent is from the environment, whatever that may be," Washbourne said. "We have a concrete hypothesis about what this environmental factor is, the gut microbiota, and how it might cause or exacerbate symptoms of autism by modulating the expression of key genes. We will seek to determine which genes in the brain are altered by the microbiota and how this might lead to altered behavior."
Over the long haul, Guillemin said: "We'll be asking: How can we manipulate these communities? Are there ways to introduce beneficial microbes through probiotics that could ameliorate deficits in normal development?"
—By Jim Barlow, Public Affairs Communications