Texas A&M University
Dr. García is also a professor of biology at Texas A&M University.
Environmental and Genetic Regulation of Motivated Behavior
As a graduate student, there were times when L. René García—the first HHMI investigator at Texas A&M University—felt so passionate about his microbiology studies that he ran experiments and devoured papers and lectures without even breaking to eat. Yet on other days it all seemed so tedious and uninteresting that he could scarcely finish reading a journal article.
García's curiosity about his own drastic swings in enthusiasm and drive, ironically, prompted him to ask questions that have guided his research ever since. Today, his long-term goal is to understand how animals execute, regulate, and sustain instinctive behavioral decisions. "Early on in my research career, I began wondering what the source of motivation and drive was, and how they were regulated," he recalls. "At the same time, I recognized that sexual impulses are very powerful motivators, and I was curious about what makes those circuits so strong."
Flash back to 1995 when García, who was nearing the end of his Ph.D. work at the University of Texas at Austin, made a bold move: He pitched the germ of an idea for a far-out research project to Paul Sternberg, an HHMI investigator at the California Institute of Technology. Sternberg's laboratory uses the roundworm Caenorhabditis elegans to study developmental biology and neurogenetics.
García proposed using C. elegans as a model for understanding how hardwired, instinctive behaviors are regulated and how they are modulated by environmental factors. García focused on a specific event in the male worm's mating behavior—the extension of its copulatory structures when they penetrate the vulva of his mate—as a surrogate marker of innate drive.
His plan was to search for mutant male worms that were continuously in mating mode even when there were no behavioral cues, such as the presence of a potential mate. "Paul gave me some normal worms, and I went back to Texas and just watched them. I noticed that rare males displayed spontaneous mating behavior, and I thought I could isolate the mutations that increased the frequency of this abnormal activity," says García. After finishing his Ph.D. studies in Texas, García made the journey west to join Sternberg's lab at Caltech as an HHMI postdoctoral fellow.
While at Caltech, García identified many behavioral mutants, some of which, he says, "wanted to have sex all the time. Their behavior persisted even though there are molecules that say if the conditions aren't right, don't do this—even if you're right next to your mate." Using these aberrant worms, García set out to dissect the regulatory circuitry in the worm's nervous system that normally suppresses inappropriate mating.
His studies showed that normal male worms extend their sex organs, the spicules, only when they make contact with their mate's vulva. But his experiments also showed that a large fraction of the mutant worms extended their spicules more or less permanently, in what García likens to a muscle seizure. He reasoned that this odd activity is caused by genetic mutations that disrupt the timing of mating behavior.
After setting up his own lab at Texas A&M; University in 2002, García set about finding the molecular players responsible for the abnormal behavior he saw in his mutant worms. He and his students have since characterized several of these mutant genes, including unc-103, a voltage-gated ion channel similar to a human protein that helps regulate heart rhythm. In male worms, mutated unc-103 can cause inappropriate sexual excitement.
Interestingly, García's team also identified a mutation in another molecule that actually mimics the effect of food deprivation (which shuts off mating behavior in normal male worms) and halts muscle seizures. Conceivably, says Garcí a, knowledge gained from studying these simple circuits in the roundworm might be used to curb unwanted cell excitability in medical conditions, such as heart arrhythmias. "How does the excitable cell regulate itself?" he asks. "Is there a pathway that can suppress this activity that could be used to treat people?"
García is now tenaciously working to reveal all the components of these sex-and-feeding behavior circuits in C. elegans. "What I hope to do during the next five years is to identify the actual intracellular players in muscles and neurons that are being activated and to understand how they can be manipulated."
He will then try to recapitulate those findings in a vertebrate genetic model system, such as the zebrafish. By doing such experiments in the zebrafish, García and his collaborators will be able to see if what he has learned about the regulation of cell excitability in worms applies to the hearts and minds of higher organisms.
His ultimate goal is to learn how the nervous system responds to a combination of genetic programming and environmental factors to sustain innate and evoked behaviors. It may take much longer, he concedes, to be able to explain why people are inspired by their work one day and bored the next.