Episode 04: Hey-Kyoung Lee, PhD

The following interview was conducted in-class, during the Spring 2021 session of Hidden Figures: Brain Science through Diversity, taught by Dr. Adema Ribic at the University of Virginia. What follows is an edited transcript of the interview, transcribed by Rhianna Bhatia and Sydney Anderson, who also drafted Dr. Lee’s biography. The final editing was by Dr. Adema Ribic. The original recordings are available in Podcasts.

Dr. Hey-Kyoung Lee is a professor of neuroscience at Johns Hopkins University School of Medicine. Her current research focuses on the mechanisms of cross-modal plasticity between visual and auditory systems. Dr. Lee studied Biology as an undergraduate student at Yonsei University in Seoul, Korea before obtaining a Ph.D. in Neuroscience from Brown University. While at Brown, Lee studied mechanisms of synaptic plasticity in the lab of Dr. Mark Bear. She developed a chemical protocol for induction of long-term depression (LTD) in acute hippocampal slices during her time there, enabling detailed molecular and biochemical studies of LTD. Dr. Lee completed her postdoctoral training at Johns Hopkins, under the mentorship of Dr. Richard Huganir, during which she studied hippocampal plasticity.

Dr. Lee joined the faculty in the Department of Biology at the University of Maryland College Park as an assistant professor and was later promoted to the rank of associate professor with tenure.  During her time there, Dr. Lee studied experience-dependent plasticity in the visual cortex. Dr. Lee moved to Johns Hopkins University later on and is now a Full Professor of Neuroscience (with tenure) at JHU.

Dr. Lee’s lab at Johns Hopkins studies synaptic plasticity at cellular and molecular levels, looking at how molecular changes at the synapse contribute to the formation of memories. More specifically, her lab uses techniques such as imaging, electrophysiology, and biochemical and molecular analysis to investigate different mechanisms of synaptic plasticity, such as long-term potentiation and long-term depression. Dr. Lee’s lab focuses on cross-modal plasticity, which she defines as how the brain adapts and changes to optimize functioning when a sensory modality is lost. Dr. Hey-Kyoung Lee has had a prominent impact on the field of neuroscience, with over 8,000 citations.

Dr. Lee, it’s great to have you with us today. Can you tell us a bit about why you became a neuroscientist?

My main interest in becoming a neuroscientist was to study how memories are stored on a biological level. We know that memories are something we hold on to dearly and that define who we are. Memories can last for decades, but all the biological molecules that can actually store memories are not that long-living. It’s fascinating to think about how the memories are outlasting the turnover of these molecules.

Was this also how you got involved in science?

I wanted to be a scientist early on in my life because my parents were scientists. My dad is a physicist. My mom studied chemistry. I was exposed early on to scientific ideas, but I was interested in biology because for me life itself is kind of fascinating. How do things live? It's very different from inanimate objects. I did my undergraduate degree at Yonsei University in Korea majoring in biology. I was curious about the brain, but I didn't know that was a realm I could actually study as a biologist. I took part in an exchange program during my junior year and I went to Brown University for a year of study abroad. I vividly remember sitting in a class thinking, “oh my God, this is what I want to do for the rest of my life”.

Is this why you chose Brown to pursue your Ph.D.?

Yes, I got very lucky - I got accepted to Brown again, which started my journey to where I am now, which is a neuroscience professor at Hopkins.

What did you study while getting your Ph.D.?

I was very fortunate to study in the lab of Mark Bear, where we studied the molecular and cellular mechanisms underlying memory formation. I was interested in understanding how the synapses actually store our memory or experience. We know that when the activation of the presynaptic neuron and postsynaptic cell coincides, the synapses get stronger, and we call this long-term potentiation or LTP. In colloquial terms we call that “fire together, wire together,” so neurons that fire together consistently will become connected together through synapse strengthening.

What about weakening?

The opposite is also true: if you have a neuron whose firing doesn't correlate with a postsynaptic cell, then that synapse gets weaker. That's called long-term depression, or LTD. We call this “out of sync, lose a link.” I think this was actually coined by Serena Dudek, who was in the (Mark) Bear lab before me. I actually inherited her rig.

What are the effects of LTP and LTD?

These kinds of strengthening and weakening processes are driven by activity, so eventually, you can have different synapses storing different information based on whether the neurons fired together. You can actually read out the history of this neural plasticity just by looking at the synaptic strength. The size of the spines (synapses) also changes when they store information. Larger spines tend to be stronger than smaller ones and vice versa, so we can read out the anatomical changes as well.

What was the basis of your graduate work?

When you have activity, you'll release glutamate, which is a neurotransmitter that works on AMPA and NMDA receptors. I was interested in AMPA receptors because they are the ones that actually transmit the information by converting this chemical signal back into an electrical form that can propagate down the chain. We also knew that NMDA receptors are critical in driving plasticity because they can sense presynaptic glutamate and postsynaptic activity to allow calcium influx. Rapidly increased calcium can then activate protein kinases, and it was thought that they phosphorylate some synaptic protein or proteins to express LTP and strengthen the synapses. On the other hand, if you have prolonged and moderate increasing calcium, you induce protein phosphatases, which was thought to result in LTD. I wanted to understand this model better.  

Why did you choose to study AMPA receptors?

The focus became AMPA receptors because I thought this would be one of the molecules that can actually be regulated by phosphorylation and dephosphorylation. The synaptic transmission I was measuring was mediated by AMPA receptors, so any change in their function could actually translate directly into changes in synaptic strength.

Did you run into any challenges while completing this research?

I ran into some problems as a graduate student. I was naive and I thought “oh, I can do this”, but then my mentor, Mark Bear, said “hey, you have a problem there because there's this thing called signal-to-noise problem. When you're just doing electrical stimulation (to induce plasticity), you might be activating just a subset of synapses, so you may not actually have enough signal for biochemical detection.”

 How did you deal with the signal-to-noise problem?

He [Mark Bear] tasked me with developing a chemical protocol for inducing plasticity, and he thought we should try LTD, which was easier to get in his opinion because everybody else in the field was trying to get a chemical LTP protocol worked out. So, he said, “let's go through the back door and get the LTD.” I developed this protocol after several years of struggling, but it ended up on a happy note because I was able to develop a protocol where I can apply a chemical (NMDA) and produce long-term synaptic depression. I found that AMPA phosphorylation at site 845 decreased after NMDA application, and we took that as a biochemical correlate of LTD.

What research did you perform during your postdoctoral work?

I moved on to do postdoctoral work with Richard Huganir, with whom I collaborated as a graduate student, to further pursue the molecular mechanisms of plasticity. I was emboldened by the idea that I could actually detect signals with biochemical methods, so I decided to go back and revisit the idea of doing it with the electrical stimulation.

How did you study LTP and LTD using electrical stimulation?

I decided to do this very controlled experiment because I knew the signal was going to be very, very small. So, I had two slices always in the recording chamber at the same time. One of them was a control slice, and in the other one, I induced the LTP or LTD. Since they were sitting in the same chamber, the conditions were identical, so I could detect any small changes that could happen, and of course, the slices are coming from the same animal. I would collect the samples in parallel and process them for biochemistry to detect phosphorylation changes.

What did you find?

I found that AMPA receptors actually have three different states. We call the baseline state the naive state. It’s a synapse that had not undergone plasticity. With the LTD protocol, we were able to dephosphorylate site 845. With LTP we phosphorylated it. We realized that LTP, which is potentiation of the synapse from the baseline, is different from re-potentiation from a depressed state. They go through different signaling pathways. We came up with a three-stage model of synaptic plasticity, proposing how reversible phosphorylation of AMPA receptors can mediate LTP and LTD, as well as basal synaptic transmission.

Where did you work after you finished your postdoc?

I got married during my postdoc, so I was limited to where I could actually go. I looked for jobs around Johns Hopkins, which is in Baltimore City, and luckily I was able to land a position at the University of Maryland, which is in College Park. I started there as an assistant professor in the Biology Department.

 What did you research during your time at the University of Maryland?

I wanted to pursue a different system because until then I was focusing more on the hippocampus. This is a site where memories could be formed, but I was very unsatisfied by the fact that I had no idea what kind of experience or activities were actually getting to these hippocampal neurons. I wanted to directly manipulate experience which can drive memory formation, so I thought I would go to a sensory system where you can directly manipulate sensory inputs and then measure the synaptic changes in its own cortex. I decided to look at the visual system, which is a preparation I was familiar with because my Ph.D. mentor, Mark Bear, had built his career around visual cortex plasticity. I was very familiar with the circuit and the model, so I decided to start studying what happens to the synapses in the visual cortex when you actually manipulate vision. These synapses are very similar to hippocampal synapses: they're glutamatergic in nature. They have AMPA receptors, and NMDA receptors and Mark Bear’s group had already shown beautifully that they can induce LTP and LTD at the synapses in the visual cortex.

How did you go about manipulating sensory experience to look at memory formation?

I was using rodents, and I would put some of them in the dark to manipulate vision. And the nice thing about putting them in a dark room is that you can actually bring them out to the light to see whether changes could be reversed.

What was your initial hypothesis for the effects of depriving mice of vision?

My initial guess was very naive. I thought when you deprive vision, there'll be less activation of the visual cortical neurons: you’re going to drive LTD. Right? And then when you expose them to light then you’re going to potentiate all the synapses because you’re getting a lot of visual activation.

What were the actual results of your study?

Synaptic strength goes up when you visually deprive the animals, and then it goes back down with light exposure, so that was totally opposite from what I predicted. More puzzling was the fact that we used somatosensory cortex as a control, to make sure that the changes we see only happen in the visual cortex. There was a depression of synaptic transmission in visually deprived animals in the somatosensory cortex, which doesn't care about the vision, it cares about touch.

Why did you leave the University of Maryland?

I also had my child as an assistant professor. Life got difficult because I was commuting almost three hours a day, driving back and forth with a little kid back home. And sometimes there is an emergency and you need to go ahead and pick him up from daycare. After I got tenure and was promoted to associate professor, I got stuck in traffic one day driving home. And I was stuck for three hours. I had a long time to think about things. I realized I couldn't do this for the rest of my life and I decided I was going to move somewhere.

You published a lot with Elizabeth Quinlan and Patrick Kanold. Is this because you were at UM at the same time they were?

Yes, we were all in the same hallway. Betsy and Patrick are good friends. We were hanging out together all the time talking about the experiments, and that's when I forged a collaboration with Patrick, so he did all the auditory cortex recordings in vivo for us (in our later studies).

 How did you end up at Johns Hopkins?

My husband is actually a professor at Hopkins. That's why I originally went to do a postdoc at Hopkins and then that's why I stayed around. Soon after I got tenure, he got tenured at Hopkins, so I came to Hopkins.  It worked out pretty well except I had to give up tenure.

How difficult was it to give up the tenure at UM and the security that comes with it?

At Hopkins, you don't get tenure until you are a full professor, so that decision was very hard for me to make because I had just gotten tenure at UM. I was secure in my job and I had to give that all up to move to a new location and new place and start all over again. But I said that was it. I can't do the commute anymore because it was just getting too much to bear. I decided I'll take the challenge and do it, and luckily-on a happy note-I did get tenure and I ended up staying.

What have you been researching since you’ve been at Johns Hopkins?

We sense the world as a multi-sensory environment. Even a simple task like looking at a songbird singing is very complicated because you capture your visual information by your eyes; your retina captures them. And then the sound is captured by your ears. There are two distinct sense organs that are capturing different aspects of your sensory environment. And yet, you have to somehow merge them together in your brain seamlessly to reconstruct what's out there. We always thought that happened in higher-order cortical areas, but my lab has shown that it actually happens pretty early on in sensory processing.

If there’s so much multisensory interaction during sensory processing, what happens when a sensory modality is lost?

There's a lot known anecdotally and also experimentally about how when you lose vision, there's something that goes on centrally in your brain that allows the remaining senses to be processed much more effectively. For instance, blind people with perfect pitch discrimination abilities. They can also read Braille, which is tactile information. Braille is really tricky to do read, I don't even feel the bumps. This makes sense evolutionarily because you want to be able to guide behavior in the absence of the lost modality. We call this cross-modal plasticity, or in general what happens in the brain to adapt to losing a sense modality.

Do these studies generalize to people who have vision but have lost it temporarily?

Yes, we can experimentally induce rapid cross-modal plasticity in adults. A recent study has shown that temporarily blindfolding adults, and having them train Braille, increased the activation of their visual cortices. This study showed that blindfolded individuals learn to read Braille much better than non-blindfolded people, and they actually use their visual cortex to read Braille.

How is your lab studying cross-modality?

We use mouse models and optogenetics to study changes in thalamic and local inputs during cross-modal plasticity. We find that the adult cortex is plastic, you can see plasticity. Interestingly, the visual cortex doesn't seem to care if it's losing vision, but the auditory cortex-which is supposed to be processing sound-is strengthening its connections when vision is gone. The auditory cortex potentiates its feedforward input from the thalamus after visual deprivation.

Has Johns Hopkins made efforts to improve diversity in science?

They are really trying hard these days. The proportion of women faculty at medical schools is still small. Increasing female and URM faculty has been a priority for the Department for a long time. We're not where we want to be, but they are really trying hard to not just increase hiring but to provide resources for retention as well.

What is a big factor for succeeding in science?

You want to be in a supportive environment. You need a community to help you out in the beginning. I vividly remember my father who told me this a long time ago when I was a kid: we're like a little seed. You have to go to fertile grounds, even if you're a good seed, otherwise, you'll die. He said, even if you're a bad seed if you end up in fertile soil, you can grow up to be a big tree. You have to seek out an environment that can provide you with that fertile ground.

Another thing that’s important is to know to ask for help and don't feel bad about it. I think with women, we feel like we are showing weakness when asking for help, but actually, that's not the case. We need support and we need to talk about our ideas. Don’t be shy about it.

Having scientists as parents, how do you think that kind of helped or hurt your path?

My dad was a professor in engineering. He was very supportive of my path because back in Korea when I was growing up, girls were supposed to go study like humanities. My dad tried to convince me to go and study English literature and I said “Dad, no I want to study biology”. And he said, “you can do whatever you want to”. That was pretty big because some of my friends didn’t have parents that supported their desires to go into science. My mom, unfortunately, had to give up her career in chemistry because she got married.  Women of her generation were not encouraged to work outside of the house, so she became a housewife. Growing up I saw that as a really negative thing because she was super smart, and she had to give up her dreams just because she got married. I grew up thinking, I'm never going to be like my mom. My mom was especially supportive of my career because she knew how much she had to give up because of society, so she said to me, “don't do that”.  I also can't imagine my parents letting me go to the United States on my own. Because of their support, I was able to make it, so I really have to thank them.

 This interview was conducted during the Spring Session of UVA’s Hidden Figures class in 2021. Class roster:

Addis, Lucas; Ahmed, Anushey; Akram, Amman; Alam, Maisha; Anderson, Sydney; Bhatia, Rhianna; Bonagiri, Paavan; Booth, Morgan; Clarke, Casey; Fisher, Grayson; Gandhi, Shreyal; Hossain, Mohammed; Rayan; Jensen, Kate; Kim, Michael; Lahham, Zina; Lea-Smith, Kori; Leffler, Schuyler; Leventhal, Emily; Mehfoud, Matthew; Morrisroe, Erin; Pham, Twindy; Sajonia, Isabelle; Sisk, Emma; Suram, Ananya; Wang, Jessica Beth; Webster, Tessa; Wilson, Gina. TA: McDonald, Amalia. Instructor: Ribic, Adema, PhD.

 Photo by JHU, used with permission.