Annalisa Scimemi, a neuroscientist at UAlbany, explains how her lab is examining the electrical signals of the brain to gain a better understanding of how Alzheimer’s disease affects cognitive functions and behavior. She also shares how her research is clarifying the ways we encode spatial information to navigate the world around us, and how this knowledge could someday be used to train self-orienting robots.
Annalisa’s lab is working to understand how the brain processes spatial awareness — both to inform medical advances for dementia research and to advance technologies seeking to mimic the efficiency of the human brain. Here’s a look into how her team uses mouse models to answer these questions.
AS: Genetically, mice are surprisingly similar to humans. In our studies, we allow them to navigate through space, and we have them run on a treadmill that has different cues that indicate different environments. For example, there are portions with grass, there are portions with different textures or different colors. As the mice move, we record the electrical activity of cells within the hippocampus called “place cells” that encode cues that tell us where we are. This allows us to monitor how place cell formations change in mouse models with different diseases.
One thing that we have found is that allowing neurotransmitters (chemicals used by the brain to communicate) to travel further in the brain tissue is a key mechanism that facilitates our perception of space. If changes in brain structure like those seen in Alzheimer’s disease block or prevent neurotransmitters from travelling where they need to go, this affects our ability to perceive where we are.
How do you know that what you see in mice can accurately be mapped onto a human brain and connected to neurodegenerative diseases?
AS: We never know that for sure; it’s more of an inference than a certainty. It's difficult because we cannot do these types of studies in healthy versus unhealthy human volunteers. Clinical trials are limited in how many people can be involved and they take a very long time. Instead, we can use mice to repeat these experiments across a larger population, which we can follow through time in healthy and diseased states and make predictions. In the future, clinicians could see whether our predictions are accurate or not.
Studies like these are really important for informing new ways to manage dementia. If we can find therapies, either pharmacological or behavioral, that can delay the progression of the disease and keep the patients in a clear state of mind for longer— if I could achieve that in my lifetime, that would be a huge success.
What do you think it will take to answer these questions?
AS: Right now, everyone is talking about artificial intelligence and how AI could help us solve this sort of question. While AI is booming, it's also environmentally and energetically hungry. At this pace, we can't sustain the developments, so what can we do? The solution is to go back to the brain to learn how it allows us to be so intellectually complex at the energetic cost of a dim light bulb.
It can be easy to think that there's no hope, but we have to overcome that. When I was a kid, there was an environmental concern about how much light we were using and then LEDs were developed. But oftentimes, when you think that there's no solution, the solution is there and it's innovation.
Look inside Annalisa’s lab to see how her team is building novel tools to study how the brain works and how it is affected by neurodegenerative disease.
Learn more about the biology of Alzheimer’s and how the disease takes hold in this Q&A.
Annalisa’s work was among six projects to recently receive funding as part of the SUNY Brain Institute. Learn more in this Times Union coverage about SUNY’s $10 million, cross-campus investment in neuroscience, featuring insights from Annalisa.
Audio editing and production by Scott Freedman
Photo by Zach Durocher
Hosted and written by Erin Frick
Erin Frick: Welcome to The Short Version, the UAlbany podcast that tackles big ideas, big questions, and big news in less time than it takes to cross the Academic Podium. I'm Erin Frick in UAlbany's Office of Communications and Marketing.
Alzheimer’s disease is the leading form of dementia, affecting over 55 million people worldwide. Every day, scientists are making strides toward understanding what causes this disease and new interventions that could help those affected. UAlbany’s Annalisa Scimemi, associate professor of Biological Sciences and Nanoscale Science and Engineering, is among those seeking answers.
Annalisa’s approach focuses on decoding the electrical language of the brain to find patterns and draw connections between brain activity, behavior, and disease progression.
Using mice as models, her team employs a noninvasive technique called electrophysiology to detect and map electrical signals in the brain.
By comparing electrical activity in healthy versus diseased brain tissue, it becomes possible to trace not only where the brain’s inner communication channels are being disrupted, but also how altered signaling leads to changes in behavior and cognitive processes like learning, memory, sleep-wake cycles and spatial navigation — all of which are known to be affected in dementia.
Annalisa’s research has revealed an important commonality among these processes: they all happen in a region of the brain called the hippocampus.
In this week’s episode, Annalisa explains how her team follows electrical clues to interpret subtle changes in the brain that could signal disease. Their work is laying the foundation for new clinical approaches for earlier disease detection, earlier treatment, and better patient outcomes.
The implications reach beyond medicine. By gaining a better understanding of how the brain is wired, Annalisa’s research could benefit other technologies too — from artificial intelligence systems to self-orienting robots designed to survey other planets.
Annalisa’s journey in neuroscience began in her home country of Italy, where she joined a lab that explored the brain using equipment fabricated in-house by hand.
Her studies led her to London and then Albany, where she’s since built a team with wide-ranging expertise, from biology and computer science to neurology and engineering.
Together, they not only devise and conduct experiments, they also create many of the tools they need to answer research questions. Handling 3D printers and welding implements as deftly as microscopes and pipettes, her lab represents a deep commitment to interdisciplinary science — an approach that just might spark answers about the most complex structure known.
Here’s Annalisa.
Erin Frick: What was it that initially spurred your interest in neuroscience? What started you on the path that you're on now?
Annalisa Scimemi: So, for me, it was actually chance. I'm a first-generation college student, so I didn't know everything about academia, but I was curious, and I come from a family where my dad was a woodworker, so I was very good at school, but I also had a very good hand dexterity. And so my journey in neuroscience began when I visited the lab and I found a professor that was studying little molecules called ion channels using electrophysiology, but he was also building things by himself, and that was my match. So I think I joined neuroscience because I joined his lab and what he was doing really resonated with my own personal story.
Erin Frick: Your lab is working to understand communication in the brain by parsing the particular roles of different cell types and brain regions — and a major focus is dementia, in particular Alzheimer's disease. So to lay a foundation, would you give us a sense of what we do know in terms of what causes Alzheimer's disease and what does it do to the brain?
Annalisa Scimemi: We really don't know how it starts. We truly know how it ends because by the end of the disease, we have access to brains and we can check what happened, how its morphology has changed, and general structural and functional features. When we look at those brains, what we see is that there are proteins that shouldn't be there that accumulate and form some structures that are called plaques and tangles. So the brain looks a little bit shrunk and it has things that shouldn't be there. It's very difficult to go back in time and understand how these proteins started forming these complexes. So we really don't know how it develops.
There are two major forms of Alzheimer's disease, and the vast majority of people, I would say roughly 95%, are affected by a form that is called late onset Alzheimer's disease. It develops after the age of 65 in humans, and again, we have very little information. The remaining 5% of people in studies are affected by the early onset form of Alzheimer's disease. It starts before the age of 65. And in that case, there are genetic factors that can be studied in families because these factors are transmissible. And we also study them in animal models like mice because they can be engineered to have the same genetic mutations as humans. And in my lab, we tried actually to go for the form of Alzheimer's disease that affects most of the people and for which we have a very limited information.
Erin Frick: Understanding the earliest phases of a disease is important because presumably the earlier we can identify it, the sooner a patient could get treated and potentially have better outcomes. In your studies, what exactly are you looking for that indicates disease is present or is perhaps about to take hold?
Annalisa Scimemi: We look for something always keeping in mind how translatable that could be for humans. So, if I have a human, I would like to have a way of studying the development of the disease that is not invasive. I don't want to drill holes in people's heads. And so when I try to go to the lab and answer those questions, I would like to have an equally noninvasive way of studying the brain. And to do that, we need to be able to decode the language of the brain that can be done in humans using an EEG, an electroencephalogram. And so if we know what the electrical activity looks like in a human, probably we can try to track it also in a mouse. So the general idea is to understand: are there patterns of activity in the mouse brain that are reminiscent of those that we can find in humans? And if so, now, how can we intervene to slow down or hopefully even stop the progression of the disease? So the discipline of electrophysiology does exactly that.
What we have found is that there's a particular region of the brain that is called the hippocampus, that shows patterns of hyperactivity. And interestingly enough also in humans, there's a phase of Alzheimer's disease where patients are hyperactive. They keep putting things in order or they may walk back and forth to a particular room in the house. It seems to the naive eye that the person is just restless, but the behavior is just a consequence of increased electrical activity in the brain. The progression of the disease is really more dramatic. And over time there's really a loss of function, loss of independence. People are no longer able to do things that they took for granted when they were younger and in healthier states. And so we hope that by preventing the hyperactive phase, we have a window of intervention to really delay the progression of the disease.
Erin Frick: Is there anything novel about the way that your lab is looking at this disease versus perhaps things that have been done before?
Annalisa Scimemi: For us, the new approach was actually to use some viral strategies to make a healthy mouse that has these protein accumulations. And the advantage of that is when we are making that manipulation, we can follow it in time. This is to shed light on the initial phase of disease development, and ideally, we would like to have better tools to trace its progression and also better ideas to stop its progression before the symptoms are already severe. The other, perhaps unusual, thing is the use of functional studies. We use a technique that is called electrophysiology. So we like to study how the electrical properties of neurons in specific regions of the brain change as we wait more and more time after having applied these viral constructs to the brain.
Erin Frick: So, you’re looking at several aspects of cognition involved in dementia, including learning and memory, circadian rhythms - so, our sleep wake cycles - and spatial navigation. What have you learned about how these come together, and in particular, how do circadian rhythms come into play?
Annalisa Scimemi: The part of the brain that brings together all these different interests is the hippocampus, strangely enough, the same region that controls the learning, memory, special navigation. And what we found recently is that it also expresses a family of genes that are called the clock genes. So the clock genes are genes that give us a sense of time, and we know during the course of 24 hours, we have times when we are more alert. There are times when we feel we want to go to sleep. What we didn't know is whether our cognitive skills, our ability to learn, would also be changing over the course of the day. And what we discovered is that there are always optimal times during the day when we can learn, but typically our ability to remember what we did is pretty much stationary. So, when we talked about dementia and Alzheimer's disease, we alluded to the fact that often patients do things at odd times, and that is a loss of circadian rhythmicity. You don't do things at the typical time. So everything that we have learned about learning and memory now can be translated in the bigger field of dementia and Alzheimer's disease, even though it wasn't initially planned as such.
Erin Frick: The ability to navigate our surroundings and recognize where we are, something that I'd say probably most of us take for granted, it's easy to forget that there's a lot of complexity happening in the brain that allows us to do that. And I know this is a question that you're working on. So how do our brains know where we are and how can this help us remember where we were at a specific moment back in time?
Annalisa Scimemi: We are going back to the same region of the brain. It's a hippocampus. It contains cells that are called the place cells. They integrate different types of information to tell us exactly where we are right now and where we were in the past. So think for example of someone asking, where did you watch the Super Bowl in 2014? I personally would have trouble answering it. I need to think, what teams played? That was the year when Bruno Mars played Uptown Funk. Now I can really tell you where I was. That example is really interesting because it tells us all the things that the hippocampus does. It integrates information. So, information about the year, the teams, the singer of the halftime show, all those ingredients are combined in the hippocampus to give us the perception of where we were. So, we study how that ability arises in these cells.
We really try to understand how different neurotransmitters, which are the chemical substances that neurons use to talk to one another, how do they actually shape the accuracy of my memories? So to do that, we needed to have at hand knowledge of the brain anatomy. We need to know the language that it speaks, but also we need to develop tools that currently don't necessarily exist. And that is where the manufacturing part comes in. And in my lab, my team members will have an idea and then that idea materializes through the construction of different devices, electronics, and so on. It's really a lab where we pursue the question. We never adapt the question to our skills. We really want to address an unanswered question. And if we have no tools, then it means that we need to scratch our head and develop them.
Erin Frick: What are some other applications that could potentially intersect with research on spatial navigation and better understanding what's happening in our brains?
Annalisa Scimemi: So one of the connections really could be in the field of robotics. So just like we navigate through space, we may want to purchase a machine that waters our plants. That little robot needs to know where the flowers are and needs to be accurate. Or if one wants to think on a bigger scale, you can think about designing robots that can orient themselves in an unknown environment, which are not only present on planet earth, but also on other planets. So I think that the long-term applications are really broad, and that's one of the reasons that we think this is also so important. So I think we are helping both the technology development and the medical field, and that gives me hope that something good has to come out of this.
When you bring people together and they come from different disciplines, they tend to help each other a lot. Someone may be more picky with coding. Someone may be a little bit more attentive to behaviors. And so it's true that there's an aspect of serendipity, but you also have to be attentive to details because otherwise magic can happen — but if you don't catch it, and you're not alert and curious and intrigued, then it may just go away as quickly as it had come.
Erin Frick: That was UAlbany’s Annalisa Scimemi, associate professor in the Departments of Biological Sciences and Nanoscale Science & Engineering.
Annalisa explained how her lab is examining the electrical signals of the brain to gain a better understanding of how Alzheimer’s disease affects cognitive functions and behavior.
She also discussed how her research is clarifying the ways we encode spatial information in order to navigate the world around us.
To learn more about how Annalisa’s lab is using mouse models to study how our brains interpret visual cues, and the role AI could play in answering such questions, check out the Long(er) Version, in our show notes.
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Scott Freedman provided audio production and editing from the UAlbany Digital Media studio deep inside the Podium tunnels.
We’ll be back next week with another short conversation about something interesting.