Can you provide a brief overview of your research?
In general, my interest lies in understanding how a memory is made as learning induces changes in the brain. My team and I want to understand the nature of these changes. They occur at the cellular level, synaptic level or manifest across the brain. Our goal is to uncover the fundamental principles governing these changes. For example, neuronal changes should follow specific physical and biological rules, and we want to identify what these fundamental rules are.
What problem are you trying to solve?
The problem we address and the new knowledge we obtain are influenced by the techniques available to us – the quality of the technique shapes the depth and breadth of our understanding. I use a two-photon microscope to image individual synapses, which provides insights into their morphology and function. Additionally, we employ two-photon photolysis of neurotransmitters to selectively activate a single synapse. By doing this, we can understand how activity controls synaptic plasticity at the resolution of a single synapse. More recently, we have investigated how learning is represented at the cell population level, involving hundreds of neurons. Using a calcium indicator injected into the mouse brain, we monitor neuronal activity from hundreds of neurons under the microscope. Following training on a specific task, we visualize task-relevant neuronal activity and analyze patterns to discern changes in neuronal connectivity associated with learning. By identifying pattern changes linked to learning, we aim to try to elucidate the underlying rules governing these changes.
Who are your collaborators here at Hopkins or elsewhere?
In this work, I am fortunate to have many collaborators at institutions across the world, including the University of Geneva, Seoul National University, Albert Einstein College of Medicine, MIT, Washington University, and more. It is really a global network. Here at Hopkins, I am privileged to work with renowned neuroscientists such as Paul Worley, Rick Huganir, Hey-Kyoung Lee, Seth Blackshaw, Akira Sawa, and Daniel O’Connor.
What inspired you to pursue this field?
Before I became interested in neuroscience, I was studying general cell biology. I received bachelor’s and master’s degrees from Korea University (South Korea) and my PhD from the Albert Einstein College of Medicine. During the first year of my PhD, I developed a keen interest in Neuroscience, inspired by my mentor, Pablo Castillo. I found it fascinating to monitor the strength of neuronal communication through electrophysiology. This experience sparked my passion for neuroscience, leading me to pursue further research during a postdoctoral fellowship at Harvard Medical School in Bernardo Sabatini’s lab. There, I was immersed in cutting-edge science, which became a valuable asset as I transitioned to running my own laboratory.
What are the most exciting – or challenging – projects you and your team have tackled?
We have developed several new techniques. Neuroscientists and others are interested in visualizing only neurons that are specifically relevant to learning, behavior or perception. However, so far, there hasn’t been a reliable method to identify or label these neurons with high temporal precision. To address this need, we developed the Cal-Light technique, named as such because it is a gene expression system induced by calcium and light.
When an animal engages in a particular task – whatever that task may be – neurons relevant to that task become activated, leading to an increase in calcium levels. While this serves as one type of indicator, incorporating a light switch allows for precise control over what neuronal activity to capture. By integrating both the calcium and the light switch, we devised a technique capable of identifying active neurons in the animal. Our initial findings were published in 2017, and we have since worked on refining this technique, culminating in an improved version in 2022.
We also devised a technique called “iTango” (inducible Tango), building upon the Tango technique pioneered by Richard Axel’s lab. They coined the name “Tango” for their technique because it reflects a protein-to-protein interaction, reminiscent of a dance. Utilizing this protein-to-protein interaction, we selectively labeled neuromodulator-sensitive neurons in the brain. Many neuromodulators control mood and behavior, typically acting through G protein receptors. When the G protein is activated, downstream signaling is triggered. Our innovation was to incorporate a light switch, enabling labeling of neurons selectively activated by the neuromodulator only when illuminated. Hence, we named this technique “iTango”, with “I” stands for “inducible,” Tango. That research also was published several years ago. YouTube video about iTango
Image: This is a graphical illustration of the iTango system. DRD2-V2 tail (C-terminus of V2 vasopression receptor)-CIBN-AsLOV2-tTA functions as a main platform. Two more modules cooperate together to cleave TEVseq by reacting to either light or ligand. DRD2 a / Hyungbae Kwon
What is the most interesting thing you are working on in the lab right now?
Recently, we have worked on a few projects that are more related to cognitive learning. It is not just about simple learning tasks where you present a specific stimulus, and then the animal makes a binary decision like go or no-go. Frankly, that sort of task seemed rather dull to me. Instead, we are interested in how animals leverage existing knowledge when confronted with novel situations. Even without prior experience with a task, we believe they have the ability to draw upon existing knowledge to devise new solutions. To probe this mechanism, we trained mice to engage in various games. Among them are a number game and a kind of shape game.
Training mice to perform these games is quite challenging. To overcome this, we designed a task tailored specifically for mice. As we trained them to make decisions based on numbers, we were struck by the realization that we do not know how mice perceive numbers. While this concept has been extensively studied in humans and monkeys, number representation in the mouse brain remained largely unexplored. So, we began to study how numbers are represented in the mouse brain first. That was really new to me, and it changed the direction of our research. Subsequently, we embarked on training mice to count to specific numbers, up to 10.
While the setup for mouse behavioral experiments is not novel, we are able to image brain activity, which was not available in human or monkey studies. As we finalize our research manuscript, we have made significant findings in understanding how numbers are represented in the brain.
What advice do you have for students entering a neuroscience lab?
I believe that today information is readily accessible, and knowledge is increasingly open. Therefore, the emphasis on learning deeply is diminishing. Instead, I think what is more important is the ability to creatively synthesize and utilize this information to address various questions. I think formulating a good question is important.
How do you approach a new question or problem?
A lot of ideas cross my mind frequently. While many are dismissed, engaging with other’s research and attending seminars constantly make me think of new questions. Sometimes new questions arise when I talk with people who are doing completely different work or from visits to museums. A museum is quiet, so I am often inspired by a piece of art. Such experience helps generate new ideas.
What aspirations or goals do you have for your research?
I want to produce groundbreaking research that will be meaningful and helpful for other scientists both within and beyond my field. I hope my lab is recognized for the advancements and novel insights we have brought forth.
Do you have any thoughts about OneNeuro?
I believe the OneNeuro initiative is a good idea, as it extends beyond the confines of neuroscience. The future of science demands increased interdisciplinary collaboration, paving the way for the emergence of new and diverse fields. In this regard, having the OneNeuro program is a great start.
What do you enjoy doing in your spare time?
At the top of my list is spending time with my family. And I do enjoy visiting museums.
Above Image: Active Cell Tagging – Cortical neurons activated during the lever pressing behavior are selectively labeled by the Cal-Light technique / Jung Ho Hyun
Above Image: Active Inhibitory Neurons – Cortical interneurons involved in learning are distinguished by their magenta color among the entire active neuronal population labeled using the Cal-Light technique / Jung Ho Hyun
Above Image: A Single Neuron – A single layer 2/3 pyramidal neuron captured through two-photon microscopy / Hyungbae Kwon
Above Image: Thy1-EGFP – A brain section image from a Thy1-EGFP mouse / Kanghoon Jung