Using a Songbird to Understand Brain Development

David Clayton of the NeuroTech group is leading an effort to sequence the genome of the zebra finch songbird, an animal that has intriguing stories to tell neuroscience researchers like Clayton.

Sometime this year, perhaps as soon as this summer, the National Human Genome Research Institute (NHGRI) will release an analysis of the whole genome sequence of the zebra finch songbird, adding another organism to a growing list of animals characterized at the genetic level. The next step, according to the Beckman Institute researcher whose white paper proposal led to the zebra finch sequencing, is to add the species to another important list.

"Then we want to add it to the list of model organisms," said David Clayton, a member of the NeuroTech group at Beckman and lead author of that white paper proposal. The National Institutes of Health's List of Model Organisms for Biomedical Research complements the Human Genome Project with sequencing analysis of organisms which have characteristics that make them good models for studying scientific and medical topics, especially issues such as disease, that are related to human biology.

"There is this critical period when it is basically an adolescent when he - and only the male learns to sing - hears his tutor and forms a memory of his tutor and then he has to practice over a two-month period. Once he's learned it at 90 days of age, once he's sexually mature, it's like it is set in stone."
- David Clayton.

Clayton was quoted in a recent article in the Boston Globe as saying that "the learning circuit in songbirds is similar to pathways involved in motor skill development, such as movement, in mammals." Clayton added that the songbird is "arguably one of the few if not the best models for developmental sensory learning and it's definitely the only model for developmental vocal learning."

Information gained from sequencing the genome of the zebra finch, Clayton says, could provide valuable new insights into brain development and evolution.

"If the sequences say here is a gene that has shown some pattern of evolution or conservation, does it do what we think it does," Clayton said. "We're doing the genome of the zebra finch but we're very interested in using that as a reference point to compare other species of birds, including the emu which is the oldest out group. We have the hypothesis that there may be genes among the songbirds that have been selectively conserved and evolved to support vocal learning, for example. By looking at several songbirds and comparing them to birds that aren't songbirds, we can pull out the genes that may be uniquely relevant to songbird-specific things."

And the study of songbirds, it turns out, is uniquely relevant for understanding nervous system development, including human brain development.

"I study the songbirds because they are a useful model organism in many ways because of the way their brains are put together, because of the way that they learn to sing, and our ability to analyze their behavior and vocal communication," Clayton said. "The questions that we are asking in the big picture are about how the brain works, and our strategy to get at that is to apply analytical techniques that are based on detection of specific gene products and analysis of activity.

"So we are trying to gain insights that will ultimately be relevant to how the human brain works."

Clayton is a professor in the Department of Cell and Developmental Biology whose research, as his Web site states, "merges neuroscience, genomics and ethology to understand the brain." Clayton's work focuses on the zebra finch as a model organism for study; it blends biology, neuroscience and genetics into a research area that he describes as neurogenomics.

"The nervous system and the genome are the two major control systems in complex biological organisms," Clayton writes on his Web site. "My research is directed at the interface between the two."

Clayton has a degree in biochemistry, a Ph.D. in molecular cell biology, and a longtime interest in neuroscience and psychology. While earning his Ph.D. at Rockefeller University in New York, Clayton heard a talk by Rockefeller faculty member Fernando Nottebohm, who he describes as one of the founding fathers of the study of songbirds as a model organism.

"There were several attributes of the songbird that were really attractive for research," Clayton said. "At that time they had just identified these nuclei in the brain, these discrete areas that control singing behavior and sound learning. And because we know where to look in the brain, that's one big advantage if you're trying to do something like gene expression and biochemistry. I got fascinated by that."

Clayton's research has focused on zebra finch songbirds because, as he wrote in his white paper to the NHGRI, the birds offer advantages for studying neural circuitry with the aim of "understanding the cellular events that open critical periods of development and that underlie synaptic plasticity and learning."

Clayton's accomplishments include a seminal 1992 paper that showed hearing a song of the same species activated transcription in the brain, a finding that led to a long line of research. In 1995 Clayton's lab reported on the habituation effect, a novel discovery related to how the brain stores memories.

"We found that whenever birds heard songs we detected this big change in gene expression in that part of the brain," he said. "After the song becomes familiar this song habituates, it goes away. We think the response is related to the storage of memories about the experience."

In 2001 Clayton was lead author on a paper in Nature Neuroscience that explained how and why it is that only male zebra finches produce songs (the male brain produces estrogen at exactly the right time of brain development). In 2006 Clayton and colleagues reported in the journal Neuron that, based on their study of how zebra finches learn their songs, a protein that plays a role in killing cells also was an important factor in memory formation. That finding could have implications for the study and treatment of diseases like Alzheimer's.

From his papers and articles it's obvious Clayton's research overlaps between the study of a specific organism, songbirds, and the areas of genetics and neuroscience. Clayton's work focuses on how the zebra finch brain develops, how the males learn their songs, and the symbiotic relationship between that process, brain development, and genetics.

"There is a big piece of hormone biology in here; there are big differences between the sexes, males and females, and that's interesting," Clayton said of his research. "There's a developmental story, brain circuitry, after the animal is hatched. So it's possible to track their development when they are an adolescent; that's when this big circuit forms. All those kind of complex things suggest a whole series of questions that one could ask about what controls the development of the system, why is it different in males and females, what happens when a bird sings, what happens when a bird hears songs. And we knew where to look."

Clayton said the male zebra finch learns its unique song from its father/tutor during adolescence by copying and then slightly varying the song of the tutor.

"There is this critical period when it is basically an adolescent when he - and only the male learns to sing - hears his tutor and forms a memory of his tutor and then he has to practice over a two-month period," he said. "He rehearses and what he ends up with is a good but not a perfect copy, because every bird sings his own unique song, but he ends up with his own little take on his tutor's song. Once he's learned it at 90 days of age, once he's sexually mature, it's like it is set in stone."

To study these phenomena more closely, Clayton is working with Monica Fabiani and Gabriele Gratton of Beckman's Cognitive Neuroscience group, using their EROS optical imaging technique to study Zebra finches non-invasively and in a more natural way. The birds wear a specially designed helmet that can record which parts of the brain are activated during both the phase when young males are learning a song and when both genders of the species are learning to recognize songs.

"One of our big projects at Beckman is trying to take advantage of this localization of function to analyze what happens when a bird hears a novel song and it becomes familiar," Clayton said of using EROS. "The idea there is to be able to monitor in real time, more or less, activity in the brain. If we can develop this technique we would be able to follow it in a non-invasive way over time, observing how a song becomes familiar."

Clayton's collaboration with Gratton and Fabiani was the result of the interdisciplinary nature of Beckman and some good fortune when one of his former Ph.D. students, Amy Kruse, took a job with the Department of Defense's research organization that was funding part of Fabiani and Gratton's work.

"It turns out that she became the program officer for Monica and Gabriele, and I ran into her a few years after she was out of the lab," Clayton said. "She said 'I was just down the hall at the Beckman seeing Monica and Gabriele and they're doing this amazing stuff. You ought to do it with the songbirds.'"

While it was a fortuitous coincidence, collaborations like the one with Gratton and Fabiani are part of the reason why Clayton came to the University of Illinois.

"One of the reasons I chose to move to Illinois was the Beckman," Clayton said. "I was drawn to the environment here and I've always had a presence at Beckman since I set foot here."

Clayton said the interdisciplinary approach at Beckman has been "absolutely essential" to his work.

"It immediately draws from many traditions," he added. "I think being at the Beckman has afforded access to the technical and intellectual. I've had access to people like for example Monica and Gabriele. I think this is a very important big picture kind of thing to be developing and it would not be happening for were it not for the Beckman."