How Do Memories Work?

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How Do Memories Work?

In this unforgettable debut episode of The Brink’s new podcast, BU neuroscientist Steve Ramirez explains how memories are created, stored, and recalled in the brain

February 1, 2024

Jessica Colarossi

Sophie Yarin

Andrew Hallock

You can also find this episode on Spotify, YouTube, and other podcast platforms.

Explain This! is a podcast from The Brink that helps you make sense of the world. From how memories work to the way language evolves and everything in between, we ask Boston University researchers to break down topics—big and small—and tell us how their work is shaping the future.

In our debut episode, The Brink’s science writer Jessica Colarossi sits down with Steve Ramirez (CAS’10), a BU College of Arts & Sciences assistant professor of psychological and brain sciences, to discuss his lab’s research on how the brain records and stores memories. Ramirez’s team relies on a biological technique called optogenetics that lets them view memories as physical phenomena in the brain—a process known as engram mapping. We asked Ramirez about where memories are stored, the differences (and similarities) between human and nonhuman memories, and how memory-manipulating technology could be used to alleviate symptoms of PTSD in a clinical setting.

Takeaways

Memories don’t live in a single point in the brain.
Memory is malleable—and negative ones can be updated with more positive information.
Scientists need to prepare safeguards to prevent the potential future abuse of memory manipulation technology.

Transcript

Jessica Colarossi: You’re listening to Explain This!

The Brink: Our new podcast from The Brink explores big and small pictures of research done at Boston University, from microbiology to art history and everything in between. Join us as we interview on-campus experts who break down areas of study and put their work into real-world contexts.

Steve Ramirez: Any biological organism has evolved the capacity to have memory. And I think that that’s a testament to how useful memory is.

JC: Steve Ramirez researches how memory is physically stored in the brain, and how memories can even be manipulated to alter negative or positive memory experiences. He and his team use sophisticated, genetics-based tools called optogenetics—more on that later—that essentially light up the neural pathways in the brain that holds a memory, making a memory a visible map called an engram. His research has revealed that good and bad memories actually look different in the mice that they study, illuminating the possibility of using memory manipulation as a way to treat mental health disorders like PTSD and depression. Steve Ramirez, thank you so much for joining us.

SR: It is my pleasure to be here.

JC: Let’s start out with a general question: Where are memories stored in the brain?

SR: We used to think that memories lived in some corner of the brain that you could go in and study and look at and poke at. But one thing that we’re realizing, in the past probably decade or so of research, says that the sights and sounds and smells and emotions of a memory are going to recruit different parts of the brain that are involved in processing the sights and sounds and smells and emotions of an experience. Those areas are distributed throughout the brain, so they exist in 3D. So we can think of it as, a memory does not exist as a single, XYZ point in the brain, but it exists more as this three-dimensional web activity distributed throughout the brain that brings the richness of a given memory to life.

JC: So how do memories work? Is there a physical process that takes place when you create a memory?

SR: Yeah, so there is a physical process that the brain uses to convert [an] experience and store that experience into memory. How that works is kind of the million dollar question here. You know, when you form a given memory—everything from the DNA and brain cells to the brain cell’s activity itself to how brain cells are coordinating their activity among each other—all of those different levels of analysis are undergoing some kind of change to make that experience possible in the brain. Now, how long those changes last for probably is for the lifetime of a memory, which, as far as we know, the lifetime can last for the lifetime of an individual, for that matter. So I think that the physical changes that happen are everywhere from genes all the way up to millions of brain cells coordinating their activity, like an orchestra together to make memory possible.

JC: So your lab studies this in rodents? How do you examine the memories of a mouse? And how is it different from studying memories in humans?

SR: Ironically enough, in humans, I like to think that it’s more straightforward for me to ask you, What’d you do yesterday, and that memory comes to life, right? I didn’t have to go in and do any genetic trickery or any fanciness to reactivate that memory in your brain. I just asked. In rodents, it’s a little bit of a tougher problem in the sense that they can’t talk back. So we have to go in and find these neural correlates of what we think memory is. And the way that we study it is that we start off with, I guess, a first principal assumption, which is that memories leave some kind of enduring change in the brain, like something has to happen in the brain in order for it to make memory possible. And again, what that is can extend all the way from genes to brain cells modifying their activity, and so on. But what we do is, we can go in and ask which are the brain cells that were involved in housing one particular memory, and we can genetically trick those brain cells to let’s say, glow green. Normally, the brain is going to look like this mushy pink custard under a microscope, and it’s really opaque and you can’t really make much of it. If we zoom in and trick brain cells that hold onto memories to glow green, we can take a really fancy expensive microscope where you can use that and go in and zoom in on those green brain cells that we think are involved in holding on to a memory. By doing that, we could go in and look at the brain cells that are holding on to memory and then ask what makes those brain cells different than the non-green or non-memory brain cells? Or are those brain cells behaving differently now that they have a memory, compared to cells that don’t have a memory or things like that. If we want to get really fancy, we could implant very miniaturized microscopes into the brain. They’re like, two, three grams and they’re smaller than your pinky. Also they cost maybe half of a Lamborghini, so they’re still kind of expensive. But what you can do then, is you can put these microscopes into the brain and you can watch neurons behave as an animal is forming a memory or recalling a memory or doing sniffy scratchy mouse things. But you can literally go in and look at thousands of brain cells as the animal is performing some task, and then begin correlating how the brain is making that task possible. So those are at least two ways more recently that we’ve been able to dive into the brain.

JC: Those glowing green cells that you mentioned, are those engrams?

SR: Yeah, so the engram is this idea of, the physical manifestation of memory is termed an engram. And that term has been around since the 1920s. Plato has this allegory of the wax tablet, and memory is like the wax tablet [where] experience leaves an imprint on the wax tablet for instance. We know now that memories are modifiable like a wax tablet, where it can melt and remelt, and every time you recall a memory, the wax tablet is melting, and remelting and changing. So that makes life a little bit hard, because that means that every memory is only as real as the last time you recalled it. And that kind of comes up, that brings up a couple of ironies like, you probably can’t recall the exact same memory twice. And because of that, how your brain does that is going to look differently both of those times. So that means that we’re chasing this really elusive thing in the brain, because what memory looks like in the brain is itself transforming over time. So now, is it in the DNA? Is it in how the cells are talking to each other? Is it that in the symphony that is memory, sometimes you do get the bass section playing a little bit louder, or sometimes you need the conductor to bring everyone back together. Or sometimes you go in and you need the percussion now for this particular memory—it is changing the way a symphony would be changing over time. So what an engram is, other than the physical manifestation of how experience leaves an imprint in the brain, I think that the answer is almost certainly going to depend on who you ask. And I would just say that, we certainly don’t know what an engram is yet. But we also don’t know zero. Maybe to summarize my answer, I think of it this way: we have a career of, I don’t know, a lifetime to try to solve what evolution had four billion years to produce. So there’s a lot of curveballs still to be expected.

JC: Absolutely, that’s a great way of thinking about it. And so let’s get into that more. I’m curious about false memories. What accounts for those?

SR: Yeah, I mean, I guess my hot take of the day is that every memory is a false memory. It’s just that some are more false than others. It’s kind of like the ‘you can’t step in the same river twice’ idea, and it’s kind of like you can’t recall the same memory twice. And one thing that we’ve learned is that memory is not like an iPhone video of the past where you can just hit rewind and play, rewind and play. It’s a lot more volatile than that. It’s a lot more dynamic in the sense that memories are all modifiable, and that’s good and bad. The good part is that it means that memories are modifiable in a way that could potentially be even therapeutic. So you could imagine, there are scenarios, for instance, of people living with PTSD, where we can recall the traumatic components of a memory and to potentially try to modify those components, given memory’s malleability—that’s good. Memory’s malleability can serve some kind of adaptive purpose. The bad part is that, to take it to its extreme, memories can be modified in a way that leads to just bona fide false memories of things that never happened. Usually, it’s inconsequential: I thought I left my keys on the desk, but I left the keys in the bedroom—no big deal. If it’s the difference between putting someone away for life because eyewitness testimony relies on memory, that can be a fallible thing. And then that’s what’s being used as a gold standard in the court of law. I think that it’s okay for us to take memory with a bit more of a grain of salt. And that’s okay, because I think that it’s okay for memories to be malleable for an adaptive purpose that can improve human health in some capacity, but it’s also good for us to have some kinds of seatbelts or, in a sense, caution tape around our memory when we’re using it as the gold standard for something because it is all but a gold standard.

JC: So interesting to think about. So how do you hope your research will help people with memory and mental health disorders like PTSD?

SR: For me, memory has really grown to be not just this time machine that we have in our brain where we can time travel back to the past or into the future—things like that, too—but I think of it almost as an antidote, that memory itself can be an antidote for a lot of what ails people. So for instance, to go back to our PTSD example, there are cases now of being able to modify negative or traumatic memories in a therapeutic manner, by updating them with more “positive” information. That positive can be in the form of a drug, in the form of cognitive behavioral therapy, and the works. But that takes advantage of memory’s malleability. In rodents, we can take it a step further, and say, we have a rodent model of depression or a PTSD. And we have ways of artificially activating positive memories, which seems to immediately get rid of the symptoms that are associated with those disorders. So the powerful thing there is that we’re not just looking at memory as a thing where we can time travel back to a moment in the past, but landing at that moment in the past can bring about feelings of increased motivation, feelings of giddiness, things that bring us joy in life. So we think of it here, by analogy in rodents, that because we seem to have this toggle over memory where we can artificially turn on positive memories, we can use that as an antidote against certain symptoms that we think are associated with depression or with anxiety. And the flip side of that is true, too, where we have rodent models, for instance of certain disorders where we could go in and identify the cells that we think hold onto a negative memory. And we can turn those cells off to prevent that negative memory from coming back, which seems to improve the animal’s welfare, or it seems to improve the animal’s sociability or motivation, or different readouts like that.

JC: Do you ever worry about this kind of technology, memory manipulation, getting into the wrong hands?

SR: Yeah, I think of it this way, to use an example, we’re like three quarters water, we drink water every day, water is like the most nourishing elemental thing that we know of. You can either use it for sustaining life, or to waterboard someone. So if something that elemental can be used for good or bad, then I think anything can be used for good or bad. And that’s all the more reason for us to come up with some kind of societal-level infrastructure to give us seatbelts to prevent the misuse of memory manipulation, if and when it becomes a thing. It’s not something that we can do on a whim in people the way that we do it in mice nowadays. But I don’t think that it also breaks any law of physics to say that it will be a possibility, if not an inevitability, in people one day, probably within our lifetime. So let’s think about what those seatbelts look like to prevent its misuse: One answer I have is to administer memory manipulation in a clinical setting. You administer a memory manipulation to the person living with a given disorder that seems to be impairing their daily routine, or their health, or both. So then, in that sense, if you’re a good psychiatrist, you’re not giving Prozac or lorazepam to the whole population of Boston; you administer it to the people in Boston living with anxiety and depression, for example. I think that memory manipulation would be the same thing, where you administer memory manipulation to the clinically relevant population whose wellbeing would increase as a result of its administration, and not just kind of a blanket ’come in here and we can Total Recall your memory so that now you leave thinking that something happened that actually didn’t happen.’ Because then we run into all the ethical dilemmas and misuse as well.

JC: So how far are we from translating this technology to humans?

SR: We’re not that far off. And I think it will depend on how our tools advance and the need for it. So for example, there’s a Canadian neurosurgeon from the 1950s that was treating patients with epilepsy and to treat patients with epilepsy, [he would] go in, perform open brain surgery, stimulate different parts of the brain—and the person can be awake. There’s no pain receptors there. And [he’d] ask the person, Do you feel like a bout of epilepsy is about to occur or not? If they say yes, it’s a problematic part of neural tissue [and] you scoop it out; if you say no, you keep moving. But it was a way of going in and trying to triangulate what’s producing the epilepsy and can we get rid of these parts of the brain that are debilitating the person? A subset of those people, when the surgeon was applying the stimulations, would say, Doctor, I have no idea what’s happening, but I randomly remember I’m walking alongside my cat and my grandma is faintly in the background, and I can hear my family’s chatter and voices. Or other people would say, I’m randomly remembering a school dance and I can hear the music faintly in the background and the chatter of the people there. And I remember walking my dog. And basically, you’re inadvertently getting memory recall that’s happening here, by stimulating parts of the brain that happen to be near the parts of the brain that we study in the lab to study memory. So this was in the ’50s, where the neurosurgeon just accidentally elicited Total Recall in a subset of patients. So the proof of principle is there already, that we can do it. I think the question is more of when would it make sense to do that? Or when would it make sense to artificially activate or inactivate or erase memories in people? And the way that I think about it is that what we do in rodents, technically, is probably not going to be what we do in people, technically, because in rodents, we were just talking about implanting these miniaturized microscopes and laser beams in the brain. I don’t think that we’re going to be implanting these microscopes and things shooting laser beams in the human brain anytime soon.

JC: Speaking of technology, and these kinds of advancements, are there similarities between brain memory and computer memory?

SR: They definitely informed each other and like the whole field of artificial intelligence kind of owes a lot to what we’ve learned about the brain and brain dynamics and how millions or billions of brain cells communicate to each other to make things like memory possible, or breathing or inferring things or imagination, and things like that. So similarities and differences between brains and computers: in computers, you’ll see a lot of ones and zeros, ones and zeros; in the brain, you’ll see brain cells that are ON or OFF, ON or OFF. The difference is that even when brain cells are off, there’s still a lot happening within those brain cells that itself is storing information and processing information and shuttling information left and right. Not necessarily the case with our standard computer, unless it’s like a quantum computer or something fancy. There’s some parts of the Venn diagram that overlap slightly, and I think it just also will depend on who you ask. Some people will be like, The brain is not a computer. Other people will say the brain is a computer, just a different kind of computer. And then we get into the semantic issue of, well, what’s a computer? and so on, and then that’s it. Yeah, that’s left for philosophy class.

JC: Do plants and fungi and non-human animals have a memory, too? Do we know?

SR: Any biological organism has evolved the capacity to have memory. And I think that that’s a testament to how useful memory is, for a couple of things: it’s good to know what almost ate us so that we can avoid it, and it’s good to remember what gave us joy and pleasure so that we can seek it out more, and everything in between, right? Those are the extremes of emotion. If you zoom into a plant, and you look at its cells, and you see how those cells respond to their local environment, they’re processing a ton of information and changing as a result of the local environment. They’re all the way up to being able to orient toward or away from sunlight, for example, and then you start getting daily patterns and seasonal patterns, and so on. I have a lemon tree at home that’s like eight years old now—100 percent has memory. I can confirm firsthand that it has memory. I think it’s just [that] there are different kinds of memories. It doesn’t necessarily need to consciously recall what it had for dinner last night. There’s other ways of solving that problem that still rely on memory. But that can fly under the hood of consciousness—like consciousness is not needed for memories. Playing the piano is another example—-motor memory—-where, if anything, the less thinking you do, the better. So I think that it’s probably not too much of a hot tip to say that every biological organism has evolved the capacity to store and retain information. How it stores and retains information and how it uses that information is going to be sculpted by the environmental pressures that it evolved under. Then, in that sense, the whole universe has memory because the passage of space and time is sculpting everything within it. You know, you look at the composition of stars, and it’s carbon, nitrogen and oxygen, hydrogen, blah, blah, blah, then stars blew up, spit all of those elements all over, that became the universe. A bunch of them condensed became stars, some became the sun, some became planets. Within those planets, stuff started happening where water came about, things that resemble cells started to sort of float around billions of years ago, and then flash forward to today. You know, you get the whole biodiversity of life and so on and so forth. But in a very literal sense—this is very Carl Sagan—what happens when a hydrogen atom has 14 billion years to experiment on itself? The universe itself evolved not just us in life and Jupiter and all the constellations, but within a subset of the life that happened to come about from this star stuff came life that happened to have memory and to be able to have this record of the past that we can access and reaccess and so on and so forth. So, for whatever reason, memory is, by its nature, interwoven with the fabric of the universe, because we are interwoven with the fabric of the universe.

JC: What a wonderful note to end on, thinking about us as star stuff. Thank you so much, Steve,

SR: It’s my pleasure.

TB: Explain This! is a podcast produced by The Brink at Boston University. This episode was mixed by Andrew Hallock and edited by Sophie Yarin. To learn more about us go to bu.edu/brink. Stay curious out there, folks—we’ll see you next time.

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