Episode 22: Annalisa Scimemi, PhD

The following interview was conducted in-class, during the Spring 2024 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 Alexander Paul Velikovich, Carol Cho, Sophia Anna Meagher, Katherine Walker Hill, Ayesha Riasat, Ava Canfield, Choa Choi and Hoang Yen Ngoc Le, who also drafted Dr. Scimemi’s biography. The final editing was by Dr. Adema Ribic.

Dr. Annalisa Scimemi is an Associate Professor at the State University of New York at Albany. She began her career in Italy, where she studied Biological Sciences at the University of Pisa. Her thesis work focused on the biophysical properties of calcium activated potassium channels in human erythrocytes (red blood cells) from patients affected by Steinert disease. She then went on to the International School for Advanced Studies in Trieste, Italy and graduated with a PhD in Biophysics, studying the development of rhythmic circuits driving locomotor-like behaviors. After receiving her PhD, she worked at the University College London, where she studied synapses and neurotransmitter spillover at hippocampal synapses, and then the National Institutes of Health, where she continued this work, looking more specifically at the role of neuronal glutamate transporters. Today, her lab studies synaptic transmission, astrocytic function, and the synaptic basis of neuropsychiatric and neurodegenerative disorders using techniques such as electrophysiology, optogenetics, and two-photon imaging.

What was the moment during your education that has set you on this career path?

 At the beginning of college, I had no idea that neuroscience existed or what electrophysiology was. I studied in Italy at the University of Pisa, and the education system there was a little bit different than the US system. A college education took five years and you could repeat any exam as many times as you wanted (though I never did). There was not much interaction with professors - they would come and give the class but there was no homework. It was entirely up to you to keep up or fall through the cracks. It may sound harsh, based on what we experience today, but I think I really liked it because it gave me the confidence that I could do it because it was under my responsibility.

 To go back to your question, you needed to join a research lab to complete a research thesis. I started knocking on the door of different professors, asking exactly what they did for research. One thing that I saw was that there was a little bit of a hierarchy, and so they were either the big professors that would meet me sitting on a leather chair with a tie or there was someone that didn't even talk to me, they sent me to their lab personnel. That was already an important message for me because it meant that there was a little bit of distance, and I needed to have that casual interaction in a professional environment for the type of character that I had.

In the end, I knocked on the door of a professor that I didn't know. The rumor among the students was that he was a tough teacher. He met me in the lab, not in any office, and he was preparing electrodes with his hands. I'm a first-generation student; my dad was a woodworker, and I was used to doing things with my hands. I was used to tinkering. So, when I saw this scene, I saw someone who had the knowledge of a professor but also the humility of an everyday person, and there was someone who could provide me knowledge while also relating to my practical traits.

What led you to go into research as opposed to medicine?

I didn’t go into medicine because I didn’t want to hold the responsibility of someone’s life, and medicine wasn't really something that I felt attracted to. In high school I was extremely good at math, but I didn't see myself as someone who would do just math forever. I was extremely dexterous with my hands and good at putting things together - at the beginning of my studies I decided to study biology because I could do experiments instead of sitting at a desk for the whole day but the exact field of studies that I would pursue was a discovery process.

How did you end up in neuroscience?

The philosopher Thomas Aquinas once said “you can’t love what you don’t know.” The more I learned throughout my undergraduate years and then during my PhD, the more things I realized I did not yet know, and how much more there was yet to be understood. This is what led me to eventually study synapses, because I felt that there was still so much unknown in that field. However, I felt that I wasn’t just starting from ground zero - rather, I was able to contribute to a very strong foundation in the study of synapses that had been laid out by outstanding figures before me. Specifically, I was asking “why do all these things matter?” We know how neurotransmitters release quanta, how they are released into the synaptic cleft, and how they diffuse out, but ultimately, why does it matter if a transmitter diffuses for 500 nanometers, 700 nanometers or more? Why is that a relevant question? For this reason, in my lab I try to contextualize my research in living creatures and understand the consequences of what I’m studying on physiology, behavior and pathological states.

Is there a professional accomplishment that you're most proud of? And on a similar note, is there a study that you've done that's been your favorite or the most memorable?

I think you'll probably find many people who say that they're proud of all the work that they’ve done, and that's the same for me. If I had to pick, I would choose from my more recent research. A project that I thought was really fun was one in which I studied how synaptic transmission changes in the hippocampus with the circadian cycles.

Can you tell us more about these findings?

We know that throughout the circadian cycle there are many changes, like for example, hormone release. But I was trying to connect two fields that were not already closely related. We found that learning is subject to circadian modulation, but memory recall is not. For example, once you have learned something, anyone can ask you about it at any time of the day, and you'll probably be able to provide an accurate answer. However, the actual task of learning is affected by circadian rhythms. During the circadian cycle many changes happen in the brain, for example the turnover of receptors at synapses, and the alteration of how quickly neurotransmitters are removed from the extracellular space via astrocytes changing their proximity to synapses. These things affect how well and how efficiently learning can take place, and so, unlike recall- which could be performed just as well throughout any stage of the circadian cycle- the task of learning may be performed better at some stages of the circadian cycle than others. So, I thought that that was a fun project, but the unpredictability of the finding, I think, is the reason why it's so memorable to me.

What challenges have you faced and how did you overcome them?

The challenges are never ending, and they are different for different reasons. For example, I think my friends would agree that my most memorable challenge was starting my PhD because it was in a new lab. When I started, there was nothing. There wasn't even an electrophysiology table, but there was a big, big pile of boxes from the floor to the ceiling. My PI said, go and put them together, and I had never done that before. Initially the thought was daunting, but that initial reaction for me didn't last more than probably a couple of minutes. After one year, I had finally set everything in place but my progress report was limited, and I could only show one action potential. I had very little data, but what I had was that I had developed the ability to build a rig anywhere. It was a challenge, but I learned, which also really made me stronger.

What are your challenges now?

How do I transmit a passion to others that have different cultures, different backgrounds, different sensitivities ultimately? At least for me, I'm always trying to do things differently. Sometimes it works and sometimes it doesn't. Sometimes you have to accept that we all have different priorities. When I approached my PhD studies, nothing else was tempting for me. It was just the science. Not everyone is like that so I think the one thing that you learn by becoming a PI is to see things from different perspectives. When you go to college, your friends are people that are like-minded most of the time. Then you're in a workplace where that's not necessarily the case. You can have students that do research to check a box. Some of them are really passionate, others are on a different path. I think I did not have the awareness that you can do research without enthusiasm. I've always been surrounded by people that loved it, as did I. Those are the different types of challenges. I think if you have a passion, the thought about challenges is: accept them so much that you don't even think about them. At least I don't think about them. I just go straight on to the core question, which for me is what matters the most.

How would you say the field has changed or evolved since you started working in it?

The toolbox has changed a lot. For me, I think it was almost inevitable that by the time I was ready to apply for an independent position I had learned quite a bit of things, but I also knew that there were new tools that I had not tested myself.

Which tool made a big impact in your opinion?

The whole optogenetics field that came out in 2005 and that was when I started looking around for jobs when I came to the US. Shortly afterwards, you would go to conferences, and you would really feel that something was changing. I perceived it. There was enthusiasm. There was also a bit of anxiety about the fact that other tools may be perceived as less fancy. We didn’t know how to react. But there was the excitement, so I felt a little bit the same. I felt like, okay, there's something I have no idea how to use. What shall I do? I decided to embrace them without losing the strong foundation of what had learnt until that point. The field has evolved in a way that makes publications perhaps more complete, but also more difficult to read.

Can you elaborate on that?

 When you read a paper right now, there's technical jargon that essentially makes it unreadable for the non-aficionados. It takes a little bit of time to understand everything. If you read a paper by Hodgkin and Huxley, or from Bernard Katz, you’ll probably find a story that is still conceptually difficult, but so much easier to grasp and follow. I think there's different styles suited for different times so I'm not trying to be nostalgic: I think I'm okay with the way that things are done right now but it is important not to forget about the past.

What excites you about the future of neuroscience research? Are there any young scientists that you're excited to see the work of in the future?

 I think the ability to relate whole animal behaviors to circuits is what I really like to read about. I enjoy the fact that there's always a young scientist that I don't know that publishes a work that I really admire. In many places, as professors, you have the opportunity of inviting a speaker. Most of the times I like to invite people that I don't know, and these are the young investigators that do something that at first might seem completely unrelated to what I do. But then, when you start talking about each other’s stuff you often find some common paths. I enjoy fields that are really different from mine. Lately I've been thinking or not thinking but reading papers that talk about facial expression in mice.

Would you say that you take a multi-disciplinary approach in most of your research? And what other kinds of experts and professionals do you often work with?

 I've always said that if I have a lab, I want people with different skills. The difficulty that you have is that it takes a little bit of effort from everyone to find a common ground, because everyone comes with a different background strengths. I think that the field of neuroscience is diverse by definition so you want someone that has a biology background, perhaps someone with a computational background. But also an engineering background, physics, and whatnot. I would like to have people that share their knowledge but I understand it's not always easy to implement.

Can you elaborate on what it was like to be a first-generation college student?

I am a first-generation college student. I was also lucky to have an older brother. He led the path in a different discipline, specializing in physics. So I had his example, but overall, we were just trying to learn from those we admired.

Did you notice any differences with respect to the countries in which you have worked?

 From Pisa, Italy, I went to London, UK, then I joined the NIH and SUNY Albany, and decided to stay in the US. I think there are differences, for example, at the level of college education and graduate school for sure. The complaint from the students of my generation at the time was that college wasn't giving us a hands-on experience to join a wet lab or industry because we didn't have practical experiences. For me, this was such a big issue because I thought it was important to have a solid theoretical preparation before dealing with practicalities. I think it would have been much more difficult to join a wet lab without knowing exactly the reason to do certain things, and then having to catch up with the theory.

 I finished my PhD in three years, which is extremely short based on US standards. However, the postdoc period can be longer in Europe compared to the US. So by the time you get to your own independent position as a professor, you have gained the background knowledge regardless of where you have studied. The paths to science can be different but you can be a great scientist in any country.

Could you talk about optogenetics and electrophysiology? Is one of these a primary technique you work with?

I like to do slice electrophysiology because it's a technique that allows you to listen to the sound of neurons in real life. If you combine that with optogenetics, now you're listening to these neurons work while also being able to perturb how they work. The advantage of doing in vitro experiments with these reduced preparations is that you can do manipulations like pharmacology and get to a detailed understanding of specific cellular and molecular mechanisms underlying a given phenomenon. The hypothesis you make can then be tested in vivo. Having the ability to study a simplified circuit and then complement it in living organisms is an extremely powerful approach. It is true, however, that it is becoming more rare to find personnel that have slice electrophysiology skills.

Can you tell us a little bit more about neurotransmitter spillover?

 After being released from synapses, neurotransmitters can go through different fates. They can bind to transporters; in some cases they can be degraded by enzymes; other times they can diffuse away. As they diffuse, they get diluted, and activates fewer and fewer receptors. Spillover is a jargon term that we use to describe the ability of neurotransmitters to diffuse outside of the anatomical edges of synaptic cleft, which is the region of apposition between a pre- and a post-synaptic terminal.

How does the work in your lab connect to neurotransmitter spillover?

 My lab has been interested in a type of transporter that specializes in taking up glutamate from the extracellular space. Most glutamate transporters are expressed in astrocytes, but a subset is present in neurons. By using slice physiology, optogenetics and behavioral analysis, what we found was that the neuronal glutamate transporters in the striatum modulate the activity of specific subsets of inhibitory synapses. This may sound counterintuitive at first sight, but because the expression of glutamate transporters is not limited to glutamatergic neurons, these molecules can modulate GABAergic inhibition.

How does the distribution of individual molecules in presynaptic terminals affect neurotransmitter release, synapses, etc.?

The presynaptic terminal, and the active zone in particular, is the region of the synapse where vesicles fuse to release neurotransmitters. The release process occurs in response to certain stimuli, one of which is an increase in presynaptic calcium concentration. Now, this means that what is particularly important for the presynaptic terminal is where the calcium channels are with respect to synaptic vesicles. In a previous work, I showed that the typical layout of calcium channels and neurotransmitter vesicles at small central synapses relies on randomness: if you randomly distribute calcium channels and vesicles in the presynaptic active zone, every vesicle is, on average, close to one channel. That's enough to sustain neurotransmitter release.

Are there any other parts of the brain you have studied a lot, and do any standout as being particularly interesting to you?

 My lab focuses mostly on the hippocampus and the striatum, but I have worked on different preparations during my training (e.g., erythrocytes, spinal cord). The reason for moving to the hippocampus is that because it is a layered structure, it is easier to understand where inputs are, and where the outputs go. I think there has been a time when people started to move away from the hippocampus, because they felt the field had saturated itself a little bit. There was a lot being done there and a lot of unknowns elsewhere. I didn’t feel like we were done though. Overall, I like to have the freedom to study different things, so I can’t rule out I will study other brain regions in the future.

What should someone look for when looking for a good advisor?

 I think anyone can truly be your advisor. But you have to be wise in your selection. In my opinion, the best advisor is someone who listens carefully to you; they can share their experiences too, but I think good advisors give you something that is specific and special for you at a particular moment in time. I select advisors who listen to me and tell me something that isn't just a copy of what they have gone through.

Is there any other advice that you would give specifically from your side of things and with your experience?

 Perhaps the most concise version of advice for me is - to be fearless. Don't be afraid, don't be afraid of the fact that you don't know something. Go ask, talk to people. Find out by yourself. Don't be afraid of challenges. When things are too easy, they are not much fun.

If you could go back in time, would you go down the same path again?

The million-dollar question! I asked that question to my PI when I was in London. My PI was Dimitri Kullmann and I'll give you the answer that he gave me because I think it's so true. He said: “Life is like hiking a mountain and it's hard to reach the top. But when you do, and you look backward, you realize that there were so many other paths you could have taken. But if you think about it that way, you can become a little melancholic, so just look forward and be happy with what you accomplished: you are at the peak of the mountain after all”. I think in hindsight, could I have done things differently? I think that any person with a little common sense would say, yes. I would have probably made some different choices, but I really don't have regrets as I have learned through the challenges I have gone through.

What are your interests outside of neuroscience? What are your hobbies?

I grew up in Tuscany, which is located in the central part of Italy. It is known for having a lot of green areas and hills, and is the birthplace of Renaissance. What I like to do is essentially go back to my roots and have contact with art and connect with nature. Growing up I was trained as a ballet dancer, to play the piano, and to draw. With time, I decided not to be a ballet dancer and the piano wasn't that portable, but I could always have a pencil in my pocket. So my current hobby is drawing. Overall, I like the normality of life. I think I like the simple things.

How big of an impact do you see further work on synapses having in the development of psychological drugs in the coming years and in the future?

I hope to have a long-term impact on understanding the reason for diseases so that we no longer try to cure the symptom but the cause. I hope that we can expand our strategies of pharmacological intervention to something else than antidepressants.