Talking With Yangguang Ou

To be haunted, "One need not be a House," wrote the great poet Emily Dickinson in 1862, "The Brain-has Corridors surpassing Material Place." The most stubborn ghosts lurk in the mind, monsters bearing the past-traumas, fears, losses-that will not leave. We easily forget where our keys are, the quadratic equation drifts away, even the names of friends vanish. "So, why are painful memories impossible to forget?" asks UVM Assistant Professor of Chemistry Yangguang Ou. For Dickinson, the source of fear is "Ourself-behind Ourself-Concealed-." But for today's neuroscientists and biochemists, like Ou, the question is: can that hidden self be revealed-and maybe healed-by teasing apart the intricate interplay of molecules throughout a living body? And what, exactly, goes flowing in and out of those corridors of the brain?

To explore these questions, Ou and her students are building new tools and approaches to detect neurotransmitters and other important biochemicals as they move and work. Since joining the UVM faculty in 2020, Ou has focused on fashioning super-sensitive sensors that can be tailored to detect specific molecules, some in lab dishes, some in living mice and rats, and, eventually, she hopes, as a tool to help doctors and patients zero in on the chemical basis of mental illnesses and other ailments.

UVM science writer Joshua Brown sat down with Yangguang Ou to talk and learn more about her research.

What are you creating in your lab?

Ou:Inside glass capillaries, we make sensors one-eighth the diameter of a strand of human hair. They're actually lots of carbon fibers interwoven together, almost like cloth. And each bundle of fiber, just seven microns across, works as an electrode. We hook up this electrode to a custom-built instrument which allows us to control the charge on the surface of the fibers. With these tools, we can detect specific molecules in a brain or other organs; or it could be contaminants in wastewater; or fatty acid molecules produced by the gut microbiome. And we can measure neurotransmitters signaling in the nervous system.

How does a chemist become interested in the neurobiology of mental health?

Ou:I've always been interested in neuroscience, which is what I studied as an undergrad at Florida State. My training has always been interdisciplinary and our group on campus here is very interdisciplinary too. The chemistry that interests me is how do we modify the surface of this carbon fiber to make it selective, to target and attract different molecules? Of course, each question that we're interested in-for example, "why are painful memories hard to forget?"-is very complex. It's never just one biomarker at play or one receptor. We're talking about multifaceted systems. But we know so little about the underlying chemistry, that it's helpful to start simple and say, 'okay, what is the role of this one biomarker? Or these two biomarkers, and how are they interplaying together?"

Can you share an example from your work?

Ou:Sure. We had a publication recently, led by an undergraduate chemistry major, Isabella Schapira '22. Our team made a sensor for tryptophan, which is an essential amino acid that you take in through your diet. Turkey, for example, is really high in tryptophan! And tryptophan is a precursor to serotonin-an essential neurotransmitter in the brain, what some people call "the happy molecule." So, understanding how tryptophan works, where it goes, and in what concentrations, may give us a new window onto important health problems. Depression, autism, and other disorders all involve neurotransmitters directly synthesized from tryptophan, including serotonin.

And what's interesting is that most of the serotonin in your body is not in your brain. It's in your gut. About 90 percent is in your gut. And it has very different purposes in the gut and in the brain. So, the body has to keep them compartmentalized: serotonin does not cross the blood/brain barrier.

But tryptophan has been hypothesized to cross this barrier. So, we're interested in how much tryptophan crosses into the brain. And how do stress and exercise influence that? If you train a rat and allow it to do two hours of running exercise, it significantly increases free tryptophan in the brain. Most of the tryptophan in your body is attached to proteins, like albumin, that are always circulating in the blood. The proteins carry the tryptophan to the blood/barrier but then only the tryptophan crosses over-and the free tryptophan is what our sensors can detect.

And all the bacteria in your gut-some healthy, some harmful-regulates the breakdown of tryptophan. So, if the gut is breaking down tryptophan on an alternative chemical pathway or breaking lots of it down to make whatever serotonin is needed in the gut, there may be less of it to travel through the blood into the brain to make brain serotonin-to keep you happy. Low serotonin in the brain is linked to depression.

So, your gut microbiome controls your mood? Like, you think what you eat?

Ou:There's definitely bi-directional gut-brain communication! In my doctor's office, there's this sign that I absolutely love, and it says, "let medicine be your food and let food be your medicine." That's a big motivation for me: how can nutrition impact mental health? How can diet and stress impact biomarkers and neurotransmitters like serotonin and tryptophan? And that's where we come in: we want to make implantable sensors that allow us to get quantitative evidence for the role of tryptophan and other neurotransmitters. We'd like to get a more accurate view of this dynamic gut-brain communication. Every person is different, and we'd like to help be able to personalize treatments based on a direct understanding of their biochemistry.

How does this connect to one of your research questions: why are painful memories impossible to forget?

Ou:Post-traumatic stress disorder-PTSD-is one of the disorders I'm really interested in. One of its hallmarks is patients have flashbacks. They can't seem to forget the trauma. I'm curious about why that is and what the chemical pathways are that cause this. We know that the pain and stress of trauma release huge amounts of neurochemicals including naturally occurring painkillers, neuropeptides-to stop the pain, of course. But these peptides also are connected to memory and memory formation. We have a lot to learn, and we think our rapid biosensors will be able to help us understand more of how this all fits together.

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