Sheffield Lab: Understanding the neuroscience of memories

Editor’s Note: This is part of a series called Inside the Lab, which gives audiences a first-hand look at the research laboratories at the University of Chicago and the scholars who are tackling some of the world’s most complex problems.

Our memories form our sense of self, and when they are disrupted—through conditions like Alzheimer’s disease and post-traumatic stress disorder—our quality of life can be greatly affected.

University of Chicago neurobiologist Mark Sheffield wants to understand how memories are created, stored and retrieved at the biological level. Using imaging techniques and a virtual reality environment, his research lab measures the activity of neurons and their connections within the brain. The goal is to understand these complex memory processes to better treat conditions that affect memory.

To learn more, we spoke to Sheffield, an associate professor of neurobiology, as well as graduate students Ariana Tortolani and Julliana Ramirez-Matias.

Where are we in understanding just how the brain works?

Sheffield: We’re just scratching the surface. We have good ideas about how we think memory works, but testing the ideas—that’s the difficulty, given how many neurons there are and how many connections there are. 

Tortolani: We are at the point of asking simple questions, like what your brain does as you walk to a coffee shop. It seems like such a simple task, but there are so many complexities in the brain with how neurons fire and interact, and how that guides and impacts behaviors. It’s just really interesting. 

Why don’t we understand everything about the brain yet?

Sheffield: We have frameworks but we need better technology. We need to be able to understand what all the neurons are doing at any given moment, what’s modulating them.

Beyond that is bringing all these levels together. It takes a lot of work and focus to connect the molecular level to the synaptic level to the population level. We’re maybe 50 years away from really having a solid grasp on how it all works together as a system.

What does your lab want to know about memory, and why?

Sheffield: When you learn something new and you form a new memory, that information is stored in the brain somehow. And at some later point, you can retrieve that information. There are physical processes that underlie that. My lab is interested in those mechanisms. How does the brain do that? What happens when you learn something new? What happens when you retrieve a memory, in terms of the patterns of activity in the brain, the connections between neurons, and which parts of the brain are involved in that?

Tortolani: There are still a lot of basic science questions around how memory processes work in the brain. A lot of the work in the lab is to fine-tune our understanding of these processes and build a foundational knowledge set of what is actually going on in the brain.

Why are memories important? 

Ramirez-Matias: Memories are central to who we are. They impact how we interact with the world, and they impact the way we think and behave. Studying memories is a way to learn more about ourselves.

Sheffield: Memory can go awry in a number of different ways. To fix a damaged brain that has gone through disease or trauma and get it back to the right appropriate state requires an understanding of how the system works to begin with.

What exactly is a memory, according to neuroscience?

Sheffield: We’re still working on that as a field. There are approximately 100 billion neurons in the human brain. They talk to each other by forming connections with each other called synapses. And the total number of synapses in the brain is around 100 trillion. 

The brain is extremely complex, and information is flowing throughout all those connections in very complex ways. In neuroscience, we are trying to understand how that works and how it gives rise to everything that brains can do: all your thoughts, memories, feelings. And we do that by looking at what the brain is doing, in terms of patterns of activity and the connections between neurons.

Where are memories located in the brain?

Sheffield: Other labs have studied what they call memory engrams, a proposed physical substrate of a memory that exists somewhere in the brain. They tagged the neurons that were active during the memory formation phase. Those neurons were in the hippocampus part of the brain.

This gives rise to the idea that you’ve got thousands, if not millions of memories of your past experiences, and they’re encoded by specific subpopulations of neurons that are all connected to each other in complex ways.

Ramirez-Matias: We think of memories that are active during some experience and then re-activated when a memory is retrieved. Some of those neurons care more about particular features of those experiences, like the context that it happened in, or the physical space where it occurred. Others care more about emotion, and when we think about past experiences, emotionally salient ones are typically more memorable. 

How does the brain retrieve memories?

Sheffield: There’s a process in the hippocampus called pattern completion, and this is part of how we think memories are retrieved. When you are in an environment, there’s something that we call a cue—maybe it’s a visual cue—that might remind you of something. The cue allows you to retrieve a memory. And it does that, if it works correctly.

But you can have a single cue that triggers the hippocampus to then complete the pattern of activity that retrieves the full memory. We call that pattern completion. The wiring in the circuitry that exists there allows for that process to happen. Sometimes, when you trigger the system, you’re not providing enough information to the hippocampus for it to be able to complete that pattern and retrieve that memory.

That’s why sometimes you can remember and then other times you can’t.

Why is emotion important in memories?

Sheffield: One of the things we’re really interested in is how emotion modulates memories. How does the neural activity and the connections between them allow for memories to form and for them to be consolidated and retrieved at some later time? And how do emotion and the circuits related to emotion modulate that process?

Dopamine has been associated with reward and positive feelings. There are projections from an area of the brain called the ventral tegmental area. That’s where a lot of the dopamine neurons exist, and they project all over the brain. They signal to the brain that this is a really positive experience, so let’s release some dopamine. And that’s going to modulate how the brain works.

How does your lab study memory formation?

Sheffield: One of the more interesting ways we approach this question is we have mice run around in a virtual reality environment, and we have a reward at the end of a maze. When they are done, we can “teleport” them back to the start of the maze, so that they have to approach the reward again.

What is cool about our lab is that we have this really high-resolution imaging of neuronal activity, so we can see single neurons light up as the mice run the maze. The technique we use allows us to look at 1,000, 2,000, maybe 3,000 neurons at any particular moment. We can see those neurons with our microscope, and we can see their activity. It’s like a firework display. We’re trying to ask: W, what does that population and those dynamics tell us? Can we relate that to what the animal is doing? 

What role does emotion play in memories?

Sheffield: As the animal approached the reward, the dopamine activity went up and up and up. This is the animal thinking: I’m going to get a reward at the end of this thing. And it’s getting excited by the fact the reward is coming.

Cells encode the memory in the hippocampus, and through a lot of different kind of experiments, we found out that the dopamine seems to be necessary to stabilize the memory of the animal’s experience. Positive factors in your world are important to remember for your future survival. It’s telling the hippocampus, hey, there’s a reward around here.

The dopamine is telling synaptic connections to be strong. And that memory can then be easily accessible in the future, because those synapses have been strengthened and they stay strong.

Ramirez-Matias: My research focuses on the study of neurogenesis in contextual fear conditioning. During development, neural stem cells give rise to new neurons. This mostly happens early on, but it occurs in some regions into adulthood, including the hippocampus. If mice receive an adverse stimulus, like a small shock, they generally learn to fear when they are in that context. But if neurogenesis is impaired, they feel fear in other contexts, too. Knowing how this works could have implications in treating conditions like PTSD.

What cells in the brain are important beyond neurons?

Glial cells are super important. There are 10 times more glial cells in the brain than neurons. Glial cells help neurons be healthy. They take stuff from the blood vessels and pass it to the neurons. But more and more evidence now shows that they are absolutely relevant for encoding information, for modulating how neurons work. And they’re really part of this whole picture that we know very little about.

It’s really hard to just test memory in an isolated way, because memory and all the processes associated with memory are happening all the time. You’re constantly retrieving and encoding new information.

How could your work potentially help treat patients?

Tortolani: Even when we are studying basic science questions, it gives us an idea of where we can start with therapies. If we understand that when we manipulate the neurons in one region it causes a drastic imbalance somewhere else, that might be a starting point for a potential treatment for someone to consider. 

Ramirez-Matias: In PTSD, in particular, understanding about fear and learning in different contexts could give us insight into the mechanisms that are happening with that condition, where there is constant recall of a fearful event. 

Sheffield: Memory problems affect so many people in the world But if you don’t know how the system works at the basic level, then treating disease and getting it back to that base level is pretty much impossible. You’re just shooting in the dark, and nothing’s targeted. There’s no structure there because you don’t understand the system itself.

We really need, at the foundational level, a basic understanding of these systems and how they work. If you can understand the system, you can target things and be strategic about it.