Walter Gonzalez,PhD

Think back to a time in your life when you had to give a prepared speech. Perhaps it was a class presentation in high school. Or, you might routinely speak in front of hundreds of colleagues at company events. Whatever it was, you prepared…you practiced…over and over and over. Yet, when you got up to present, it is likely that your speech still contained those little “um’s” and “ah's” sprinkled throughout otherwise perfect sentences. These are what could be called “errors” in your speech pattern, also known as speech disfluencies. It is hypothesized that these errors are caused by “noise” within brain circuitry, possibly triggered by external stressors such as the pressure of standing up in public and delivering a speech. Speaking involves many areas of the brain, all working in concert, achieving all sorts of tasks that range from remembering what you want to say to finding the right words, and then signaling to the muscles that create the sounds that form those words. It is possible to practice what you plan to say to perfection. Yet, because of the complexities involved in speech production, and the stressors associated with performance under pressure, errors still occur.

Walter Gonzalez is a new Assistant Professor at UCSF and a Freeman Hrabowski Scholar at the prestigious Howard Hughes Medical Institute. Gonzalez is investigating how errors arise within neural circuitry, and how errors are potentially corrected during complex behavior. In Gonzalez’s own words, “Currently, our research focuses on identifying how information transfer between networks of neurons controlling learned behavior is compromised by noise and how distributed neuronal networks adjust their activity to preserve behavior” (www.gonzalez-lab.com). To address these fundamental issues, Gonzalez’s lab examines the vocal patterns of a songbird, the Zebra Finch.

Songbirds are ideal for studying speech because they “vocalize” through songs that are highly reproducible. Songbirds are born knowing how to sing, but they need to learn their songs. Their songs will ultimately contain elements that are learned from ‘tutors’. A tutor is another songbird, often a parent, who literally takes the time to instruct the young bird, trial after trial, reprimanding errors until a song is learned and remembered. This is remarkably similar to human experience.

Gonzalez’s lab uses the Zebra finch as a model songbird. Zebra finches have songs that are particularly amenable to quantification because they vocalize using a clear pattern of notes such as “abc…abc…abc”. And, this is where the analysis of ‘errors’ comes in. When communication between brain areas involved in vocalization are working well, the song is clean and clear. But, if the flow of information is compromised for some reason, then other sounds are produced that interrupt the typical “abc...abc” pattern. These interruptions are similar to the human “ah’s” or “um’s”. These sounds are not learned from the tutor and can be categorized as “errors”. According to Gonzalez, errors in song are often ignored in research, treated as something that is more annoying than interesting. Gonzalez has flipped the script and studies these errors. He hypothesizes that errors will be a window into understanding how noise affects brain function.

Why has it been so difficult to study errors in brain processing? It boils down to the fact that it is extremely difficult to actually know the ‘intent’ of an animal. For example, imagine you train your dog to sit when you give a command. A trained dog would follow these commands often perfectly, but occasionally it may fail to follow the command. Is the failure because the dog had no intention to sit? Perhaps it saw a much more interesting squirrel that it would prefer to chase. Alternatively, was it because noise within a brain circuit corrupted the flow of information necessary to understand the command? There is no way to know. However, because zebra finch song is so stereotyped, it is possible to ascribe the ‘ums’ and ‘ahs’ as errors. Once behavioral errors can be defined, it becomes plausible to dissect the underlying cause(s) of those errors within brain circuitry.

The development of new technologies to measure phenomena in live animals is key to Gonzalez’s research. “My past and current research are intrinsically multidisciplinary, requiring knowledge of electronics, engineering, programming, surgical techniques, and behavioral analyses.” Gonzalez is driven to create new devices and new experimental methods that allow him to collect data in ways that were previously impossible. With new data comes new insights, and those insights drive new ideas. Here is an example. Previously, researchers had put electrodes directly into the zebra finch brain that allowed them to record from small numbers of cells. Researchers would then correlate the activity of those cells with the stereotyped production of songs. Gonzalez created a new experimental paradigm in which high-density recording elements fashioned of silicon can listen to 1000s of neurons at a time and do so from multiple brain areas simultaneously in singing birds. The importance is many-fold. When a song is produced, multiple interconnected brain areas are engaged simultaneously. The flow of information between these areas had never been directly documented. Furthermore, ‘noise’ is inherently difficult to study because it is, by definition, random and rare. Thus, one has to look across many more cells and songs to identify signatures of noise. Gonzalez’s new devices enable this new area of investigation.

Gonzalez describes what he does as fundamental science - research that is not geared toward a specific disease or therapy. He is driven to understand how the brain controls behavior. More specifically, a goal of his laboratory is to “identify the mechanism by which brain areas communicate,” which would reveal the communication protocols that neurons across the brain must follow in order to effectively produce an action. According to Gonzalez, we have learned quite a bit about the anatomy of the brain, but we understand far less about the flow of information between regions of the brain. Gonzalez makes the following analogy: the discovery of the structure of DNA was a remarkable scientific achievement. But, DNA structure alone is not very useful. It was the discovery of how DNA sequences instruct the creation of amino acids and proteins that revolutionized science. Identifying this communication protocol gives us full control of biological systems and has facilitated countless discoveries. Gonzalez emphasizes that the field of Neuroscience needs to reach that level of understanding before ‘useful’ applications can be considered. Attaining this level of understanding would be a huge advancement in brain science, a dream that Gonazlez hopes he can attain over the next 30 years of research. Yet, it is also clear Gonzalez does think about potential future applications of his research. Gonzalez envisions that “identifying the error-correction mechanisms of the brain will reveal how neurological disorder affects the brain and lead to novel therapies seeking to enhance cognitive abilities and promote recovery from disease.” Gonzalez further explains, “Ultimately, this basic understanding of brain function will open novel avenues to implement brain-machine interfaces that seek to enhance normal brain computation and prevent or reverse age and disease-related cognitive decline.”

If you have ever attended an Opera, the singers rarely make an error. Is it possible that humans can become error-free? Gonzalez explains Opera singers may strengthen their neural pathways, suppressing error formation, due to consistent, repetitive practice. And, the same may be true for zebra finch. The older they get, the more “perfected” their songs become. But, this does highlight an important difference between humans and songbirds. Unlike birds, humans don’t automatically sing to communicate; they are capable of both singing and speaking. It is hypothesized that pathways controlling speech and singing in human brains are

separate. There have been instances where a human may have a lesion in their brain that inhibits their ability to speak, yet they can still sing. Therefore, speaking and singing don’t necessarily function the same way in the brain. Gonzalez is unsure whether birdsong vocalization fully captures all the complexities of human speech. However, birdsong represents one of the most complex learned motor behaviors, which will enable Gonzalez to lift the hood and examine error creation and correction in the vertebrate brain.

Gonzalez describes a career trajectory that underscores a powerful drive to succeed from an early age. For Gonzalez, science was always an interest. But, like many young people trying to find their way, academics always had to be combined with full-time work – getting that paycheck to support himself. In college, Gonzalez describes taking classes in physics and chemistry in the morning and working 40-60 hours per week in restaurants during the evenings. One wonders when he did his classwork! Ultimately, a taste for independent research came via an encounter with a college professor, Jaroslava Miksovska, who opened her lab on weekends so that Gonzalez could try his hand at the lab bench. Like so many other young scientists before him, this was the moment Gonzalez says he fell in love with research, “Everything was new and amazing.” But, a career in science still seemed unlikely given his need to support himself. At least until he discovered that it was possible to receive a stipend for independent study, effectively being supported to work toward a PhD. This was another life changing moment. Gonzalez applied to a single graduate school, was accepted and stayed in the very same laboratory with Miksovska, where it all began. After his PhD, Gonzalez moved to CalTech to work with Professor Carlos Lois, where he expanded his scientific horizons, transitioning from pure protein biochemistry to the study of brain physiology and animal behavior. Currently, Gonzalez is a newly minted Assistant Professor in the Physiology Department at UCSF and a member of the Kavli Institute for Fundamental Neuroscience.