Journey through the Mind: Episode 4 - Featuring Dr. Denise Cai
00:00:15:13 - 00:00:40:21
Kelsey
Hi everyone, and welcome to Journey Through the Mind, exploring the life of a neuroscientist. I'm Kelsey Lucerne, I'm a neuroscience Ph.D. student and your host. Today we are joined by Dr. Denise Cai. Dr. Cai received her PhD in experimental psychology and behavioral neuroscience from the University of California, San Diego. She's now an associate professor in neuroscience at the Icahn School of Medicine at Mount Sinai.
00:00:41:08 - 00:00:46:04
Kelsey
Her lab focuses on how memories are formed and linked across time. Dr. Cai, you for joining us.
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Denise
It's so much for having me Kelsey and thanks to listeners who are listening in.
00:00:51:01 - 00:00:55:06
Kelsey
So would you mind telling us a little bit more about what your lab studies?
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Denise
Yes. So my lab studies memories and how is it that we accumulate these memories and stored in the brain and know where in the brain to go find these memories later. And, you know, it's really amazing because like, ah, across our lifetime, we accumulate with seems like an infinite number of memories. So how is it that our brain knows where the memory should be stored and and how do we file it so we can cross-reference it later?
00:01:19:02 - 00:01:29:03
Denise
And so I also think that, you know, the accumulation of these memories across a lifetime is what really defines our human experience. And so this is I'm really excited to study memories and how they're stored in the brain.
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Kelsey
Yeah. It sounds like a very complicated process. Now you're talking about we have what seems like an infinite number of memories. So how do you begin to study this in a laboratory?
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Denise
Yeah, great question. I mean, first, like, can we even agree on what a memory is? That's still a debate in the field or what is, you know, a memory representation of the brain, still a debate in the field. So our perspective is, you know, we believe that memories and experiences are encoded inspirational populations in the brain. That distributed across the brain.
00:02:03:04 - 00:02:27:17
Denise
And the way that we track how memories are stored is through these miniature microscopes. And so these miniature microscopes allow us to peer into the brain in real time. And so we study in mice. So while mice are interacting with the world, behaving, learning, we are peering into the brain and looking at hundreds to thousands of cells in real time, how they fire and respond to the world of mice interacting.
00:02:28:06 - 00:02:40:09
Denise
And so what we find is that in areas of the brain, like the hippocampus, cells are active during the initial learning phase. Many of those cells are reactivated when the animals are recalling that memory.
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Kelsey
That's amazing. And so I believe you're referencing miniscopes, correct?
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Denise
Yes. And these are miniscopes, as we call them, or miniature microscopes. And we develop open source microscopes with a number of collaborators across multiple institutions. And these miniature microscopes are made with some plastics. The sensor is like the same sensor from your camera phone. And so we build them in-house and they're very cheap and easy to use.
00:03:09:01 - 00:03:27:03
Kelsey
Wow. So I guess what when you're looking at these cells that are firing in the brain, how do you. You're saying that you think it's dispersed across the brain. So are you able to look at the full brain or do you look at a particular brain region with these microscopes?
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Denise
Yeah, great question. So with the microscopes, the ones that we use in the lab, we can only really focus on one brain region at a time. But then we can see the dynamic activity of all of these cells or ensembles that cells, groups of cells work together to encode a memory. But there are other techniques in the lab that allows to look brain wide.
00:03:46:05 - 00:04:07:08
Denise
There is a technique called i-disco. And one of the earlier versions is actually called Clarity, which is the name of my daughter. And she was named after the Brain Clarification Method. But using these brain clarification methods, what we can do is after an animal, let's say, has an interaction with the world that we want to kind of capture what cells were active while the animals were encoding that experience.
00:04:07:19 - 00:04:30:01
Denise
We can then take a snapshot of the cells across the brain by later sacrificing the animal and taking their brain, clarifying the tissue such that now we can take really fast cameras and scan through you know, the cells that were active during that time and look at all the cells across the brain and how they work together to encode a memory, for example.
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Kelsey
How do you think that would map on to the human experience? Because in these experiments, we designed them so carefully and we're isolating kind of the first one with a single memory.
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Denise
Yes. Okay. So I have a Two-Part answer to that. And, you know, so my background is actually, as you mentioned, I got my training as a psychologist and I started as a cognitive psychologist doing experiments in human psychology. And what I really care about is human memory. Right. And so we're doing human memory experiments, but it was really, really difficult to control for everything.
00:05:02:14 - 00:05:21:05
Denise
And I thought for sure, like, once we get to mice, there will be no variability because whatever you do, the mice are going to respond in the same way. So we know that's not true. There's still a lot of variability in mice, but we can take control of a lot of things, including looking into the brain. And, for example, looking at the specific cells that respond to an event and encode the memory.
00:05:21:13 - 00:05:48:10
Denise
So in humans, there's also an imaging technique which gives you less spatial resolution. So fMRI or functional magnetic resonance imaging allows you to look at brain areas that are more active and less active at certain points. And so there's a lot of data from human imaging showing that across the brain areas are more active during encoding are also likely to be reactivated when humans are remembering that memory.
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Denise
We were really grateful to epileptic patients in a lot of epileptic patients because you're trying to find, you know, what is the focal point of the epilepsy. We get these implants into the brain and researchers have taken advantage of these implants and be able to record from single neurons and actively single track, much like what we do in our mice.
00:06:08:23 - 00:06:28:23
Denise
And what they found that there are cells that respond very selectively. For example, a very popular study or famous study showed that there are cells that respond specifically to Jennifer Aniston or Halle Berry. And these Jennifer Aniston neurons or Halle Berry neurons, you know. What we think these neurons that specifically respond to encode and store a particular memory.
00:06:29:06 - 00:06:54:02
Denise
And so these studies in humans allow us to compare our results in animals. Now, you brought up a really interesting point, right? Because in our mouse studies, what we typically do and what we've been doing for the last, you know, many decades is that animals are in their home cage. Living in isolation might be just like have this boring cage and we take them into a brand new box.
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Denise
It's like different from anything they've ever imagined. We shock them and we put them back and we asked them, do they remember where they were shock? And so while this kind of paradigm, this contextual fear, condition, paradigm or other types learning paradigms have been very powerful and helping us understand how are single memories processed. Much of the work in my lab and other labs more recently over the last decade has really been focused on how do we encode multiple memories, right?
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Denise
Because as you mentioned, across our lifetime, we're constantly making new memories. You are making new memories right now. Right. And this has to be integrated with maybe what you have for breakfast and later on what you're going to do with your friends after our interview. And so how do we you know, how do we understand how the brain processes multiple memories?
00:07:35:11 - 00:07:55:18
Denise
And so this actually inspired my interest in wanting to use these miniature microscopes to be able to track multiple experience within the same animal across that lifetime. So with this miniature microscope, for example, we can put onto the head of an animal and see what they're doing on day one and what cells are responding to them, including the memory of day one.
00:07:55:19 - 00:08:07:09
Denise
And we can then also look, you know, every day at the same cells, how they're responding across many months. And so that allows us to really see how memories evolve in the brain across a lifetime.
00:08:07:22 - 00:08:34:22
Kelsey
Yeah, that's a really interesting point. I was thinking. I feel like so much of our previous learning and memory kind of dictates how we even develop new memories. So we have a negative association with something, something that reminds you of that. You might automatically form a negative association with, for example. But even just like I feel like memories in your head can almost get messy, like a smell remind you of something completely different from where you actually are at any given time?
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Denise
Yes, absolutely. And something, you know, there's a number of interesting points that you bring up. One which is memories are messy. Right? And the thing that we know most true about memories is that they are it's not like you take a snapshot of photo. And when you remember it, you remember every detail in the exact same way. Right.
00:08:53:16 - 00:09:15:04
Denise
And memories are not snapshots. Memories are not static. Memories are actually very dynamic and constantly changing as we experience new things in the world. And how we integrate what, you know, this conversation into maybe your prior memory of me. Right. You're going to continually update and how do we update new information every day? A big question in the lab.
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Denise
And so I think you're right on the money that memories are very dynamic. And it's fun to study how we update in that way.
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Kelsey
Yeah, it's definitely very interesting. And so this is a little adjacent to what we're talking about, but just even thinking about how we update our memory, I know something that a lot of people in memory focus on sleep actually, because this is hypothesized to be an important period for consolidation of memory from any given day.
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Denise
Yeah.
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Kelsey
It almost feels like though Sleep in dreams can be a time where we can update. Yes. Learning as well. I don't know if you're familiar with any studies on that or that's something that your lab tries to incorporate into your studies.
00:09:56:03 - 00:10:34:08
Denise
Yeah. Thanks, Kelsey for that question. So that's a lot of my Ph.D. work was on how to sleep affect memory. And so we and others have shown that, you know, sleep is really important for, as you said, consolidating the memory, stabilizing the memory. And one way we think that that occurs is that after learning during sleep, your brain kind of quiets down and allows the cells are previously active to be reactivated or in the literature called replayed such that the reactivation of their cells and being active together will strengthen and stabilize that cell to represent that memory And a lot of this happens during slow wave sleep or deep sleep.
00:10:34:16 - 00:10:58:22
Denise
And this has been shown in both humans and in mice. And so in addition to that, what I showed in my Ph.D. was that during REM sleep, it's really important because it not integrates what we just learned with our past experience. We were actually trying to study creativity, said this, and we defined creativity as taking things that were previously not associated and associating them in a new way so that they can solve any problem.
00:10:59:07 - 00:11:20:14
Denise
So in our human studies, we showed that subjects who took a nap that included REM sleep were able to better use what we just the information we implicitly gave them. They're able to use that to solve kind of a new problems in new puzzles after their nap compared to subjects that did not have REM sleep. So it's really funny because, you know, that was published in 2009.
00:11:20:22 - 00:11:43:17
Denise
I did my postdoctoral studies and totally something else. And when I started my lab, we started asking, well, how do we link memories across time? And the question that we're very interested in is kind of something you alluded to earlier, which is that after negative experience, if something bad happens to you, you want to be able to link it back in time and know what was that bad thing that was a predictor, that bad thing, and linked the two things together.
00:11:44:12 - 00:12:08:04
Denise
And some preliminary data in the lab suggest that the more negative a thing that happened to you or to our mice, I should say. That not only are they going to reactivate or replay what just happened or potentially stabilize that memory, but it's almost like the brain searches for past things to to relate the two events together and link the two events through reactivation of passed events.
00:12:08:13 - 00:12:30:04
Denise
And so now we're really interested in like, okay, so we see this happen during that period, a period where animals are mostly sleeping. And so now we're really looking at to see, you know, is this similar to human studies where maybe during slow eat sleep there is a lot of reactivation of that recently meant to stabilize that memory and maybe did REM, rapid eye movement, sleep is the sleep state that's rich in dreams.
00:12:30:11 - 00:12:37:23
Denise
Is that the brain state that in the animals you're reactivating not only what they just learn, but also reactivating past memories, creating new associations.
00:12:38:11 - 00:13:03:16
Kelsey
That's really interesting. I can't help but think of for these animal models. We're talking about your conditioning. You could kind of very easily see how that would relate to like traumatic events like human or PTSD. And so I wonder if we can identify these critical periods of memory consolidation following traumatic events. That would be a good time for intervention to prevent something like PTSD.
00:13:03:17 - 00:13:32:09
Denise
Yeah, absolutely. So one hypothesis is that we're testing the lab that we recently got funding for is kind of this relationship between how traumatic an event is and the reactivation of that trauma memory. Essentially, during these sleep stays and how long that lasts. So one might imagine and again, this is something we're ongoing work in the lab that we're testing that after a traumatic event that event is more likely to be reactivated for longer periods of time.
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Denise
And if you know, every day your recent events get reactivate it and your trauma memory is also getting reactivated. You can imagine that that trauma memory, that fear, that trauma memory might get linked to events that have nothing to do with the trauma that might maybe we don't know. Right. But we're hypothesizing that may trigger PTSD like symptoms of anxiety or stress with things that are unrelated to the original trauma.
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Kelsey
That's really interesting because I think that's such a key characteristic of PTSD or these triggers that some of them perhaps you can draw a clear connection like a car backfiring or etc. and some of them seem so unrelated, it'll be something that happened the day after.
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Denise
Yes.
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Kelsey
A Smell like something. Completely trigger this traumatic memory.
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Denise
Absolutely. Another area the lab is looking at, you know, so my lab is very interested in mechanisms of, you know, modeling PTSD in mice right after an acute traumatic experiences. What are the changes in the brain that happen that lead to Long-Lasting stress responses later on? And some of the findings in the lab suggest that it's not only the memory of the trauma that contributes to PTSD like symptoms later on, but there are other changes in the brain that are unrelated to the strength of the memory of the trauma that might promote sensitized responses to stress later on.
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Denise
And that's an ongoing area in the lab as well.
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Kelsey
Wow. I mean, that's incredible. I find that so interesting. And it makes me think, too, of how in a lot of these psychiatric conditions related to stress or PTSD, the diagnosis of these in humans is so nebulous because we rely so heavily on self-report. But one of the metrics is recurring nightmares or even just the presence of nightmares.
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Kelsey
It makes me wonder how that how the difference between in REM sleep, perhaps the normal chain for consolidating the memory versus the nightmare and that sort of stress response.
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Denise
Yeah.
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Kelsey
While you're sleeping.
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Denise
Yeah. And, you know, one of the hypotheses that we're interested in is that, as you mentioned, right. So one of the cardinal symptoms of PTSD is disturbed sleep and recurring nightmares, intrusive thoughts even in the daytime. And and we wonder if, you know, part of the the stress and anxiety may be a result of the recurrent nightmares and the disturbed sleep.
00:15:51:02 - 00:16:07:11
Denise
Right. We know from a lot of research that disturbed sleep leads to increased stress. And so we wonder if the recurring nightmares actually exacerbate the stress, the anxiety. And it might also be very cyclical that the stress anxiety also that exacerbate and maybe increase nightmares.
00:16:07:11 - 00:16:08:22
Kelsey
And positive feedback loop.
00:16:09:05 - 00:16:11:11
Denise
Positive Feedback loop. That's right. That's right. Yeah.
00:16:24:23 - 00:16:46:06
Kelsey
Yeah. I wanted to transition a little bit into kind of how you came to be a neuroscientist. I mean, you're you're doing very incredible work at a great institution. Did you envision this for yourself when you were like a little girl? You always thought, I'm going to grow up to be a famous neuroscientist.
00:16:47:05 - 00:17:10:00
Denise
Definitely not. So I can at least from college, I was pre-law and I was planning to go to law school. And my honors thesis was in psychology in the lab in which I worked at the district attorney's office. And I volunteered in some neuroscience labs and psychology labs for fun-zees. It's like I love being part of experiment and and I love designing experiments to tap into human behavior.
00:17:10:00 - 00:17:36:20
Denise
And a lot of it was related to you in psychology in the lab. Right. Eye witness memory testimony, for example. How accurate is that? How do you how do you how do district attorneys make decisions about assault, rape cases? You know, are they weighing the evidence fairly without bias? And, you know, that was what my honors thesis was on. I also happened to work in a neuroscience lab looking at brain plasticity in human deaf subjects and how being born deaf might change plasticity in the brain to compensate other brain regions.
00:17:37:04 - 00:17:54:23
Denise
So I I did the research for fun and, you know, in part I still remember when I was undergrad and I thought, okay, I'm spending a lot of time like doing research. And I really like it, but I want to be a lawyer professor. And I was like, oh, lawyers are way more fun than I want to hang out lawyers.
00:17:54:23 - 00:18:07:04
Denise
And I thought, you know, like this research thing like it's just a hobby. Okay. So then I applied to law school, and while I was visiting law schools, the highlights were just like, you know, random conversation that I had in coffee shops or on the bus
00:18:07:04 - 00:18:07:20
Kelsey
00:18:08:06 - 00:18:27:15
Denise
or to people that I met at these universities talking about memory, brain behavior. And I was one of those, like, really weird kids that, like, I would stay up late at night trying to make, oh, my gosh. Like, it'd be super cool if we could understand, like, how this led to this. And I would stay up late trying to come up with experimental design, and then I would wake up early the next morning like, Oh, we got to have the perfect experimental design
00:18:27:15 - 00:18:28:03
Kelsey
00:18:28:10 - 00:18:49:05
Denise
Like, this is how we solve this problem. And so as I was really thinking about, like, getting ready to go to law school, I realize that's not where my passion lied, right? And I realize a big part of me choosing law school was because, you know, growing up in a Chinese family, my parents need to be a lawyer or a doctor.
00:18:49:14 - 00:19:10:11
Denise
And as I definitely don't want to go to med school, I want to be a lawyer then. But when I really did a lot of self-reflection and soul-searching, I realized my heart is in asking questions about the brain and in research. And so I reached into my law school applications and I apply to grad school. So your question of like, how did I get here?
00:19:10:12 - 00:19:27:00
Denise
Right. So I think like the answer is every time someone tells me I can't do it, I can't help but to go and try to do it. Right. And I feel like that's like maybe that's the theme of my, my scientific career. And so, you know, people are like well, there's no way you could get into grad school.
00:19:27:00 - 00:19:51:10
Denise
You have no science background. You have never taken a math class. You never you know, like I was ....., and but as I was just apply anyway, even though like I don't meet a lot of the requirements and I was very fortunate to get into grad school and I went to an UCSD for my Ph.D., as you mentioned, and I started out as I mentioned, I started out as a cognitive psychologist wanting to understand human memory.
00:19:52:03 - 00:20:15:05
Denise
But one of the challenges, one of the many challenges was like, I wanted to get into the brain. Like I was like, okay, we can manipulate this behaviorally. Then we get out this outward, behaviorally cool. But like how does a brain do that? And I remember then there's a grad student in the program. His name's Tristan Shuman who is now faculty in neuroscience.
00:20:15:13 - 00:20:27:02
Denise
He was then my grad buddy, and he was more neuroscience focused. And he said, Did you know that you can change one molecule in the brain and that make you know, are animals smarter and they can perform tasks.
00:20:27:02 - 00:20:28:17
Kelsey
00:20:28:17 - 00:20:48:13
Denise
Change one molecule and like you can we can make memory better like this. Like, blew my mind we couldn't test this in humans. And so I begged this, like, animal lab, and I said, can we do some kind of collaboration? Like, can we just try to replicate what we see in humans? In your mice, like the behavior and then look into the brain to see, like, how this happened?
00:20:48:13 - 00:21:08:05
Denise
So that's actually how my PhD project about it was just really led by the questions and you know, and, and so his name is Stephan Anagnostaras. And he said, sure, come alive. And like, let's try to see if we can replicate what you find in humans. And so people said, There's no way to me. So you can do both human and rodent work for me.
00:21:08:05 - 00:21:13:00
Denise
There's like, no way. And I was like, well, then let's just do it, you know?
00:21:13:00 - 00:21:13:08
Kelsey
So.
00:21:13:11 - 00:21:28:09
Denise
So I did so half of my Ph.D. work was in humans, the other half was in mice. And it was, you know, trying to run parallel studies so that we can do reverse translational studies. And, and whatever. We kind of humans try to look in the brain in mice, and then we find that in mice bring it back to humans.
00:21:28:15 - 00:21:44:05
Denise
And that's my PhD was about. And then, you know, but I still had never actually opened the brain. I was just in behavioral studies. And for my postdoc I also wasn't have like to do human studies or mice. People kept telling me I can't do both so fine. And I end up going to Anagnostaras lab.
00:21:44:12 - 00:22:07:05
Denise
And I was just like so magnetized by his passion for science. And also he's like multilevel approach of answering questions like gnarly. But it was a, you know, at the time is mostly molecular biology lab. And again, I've never taken a bio class, right? So like, oh, crap. Like, how can I possibly make it? And again, people are like, oh, funny psychologist.
00:22:07:05 - 00:22:32:11
Denise
Like, can you really understand mechanisms of memory when you have no biology background. And it was really through collaboration and, you know, not being afraid to ask for help. I ask a lot of people for help to teach me and to rely on the strengths of other people. And so it was through that that we began to really understand what are the molecular cellular underpinnings of how memories really cross time.
00:22:33:02 - 00:22:55:02
Denise
That led me to ask, well, this leads to a very interesting hypothesis that maybe the way that we link memories across time is through this overlapping representation of between neural ensembles. So one memory and another memory might be linked to class time because they share some of this in cells and that memory representation but how do you track memories across time as we we just talked about?
00:22:55:13 - 00:23:18:23
Denise
And at that time, there is an amazing invention at Stanford University, this miniature microscope and and we're like, oh my gosh, like that would be amazing if we could use this tool. This tool was commercialized and at the time was just really outside the range of what was accessible financially for our lab. And, you know, I think people said to me, there's no way you can use this fancy imaging tool.
00:23:18:23 - 00:23:37:00
Denise
You're not engineering. You don't have optics background. You're just a psychologist. Like, all right, once again, let's just show you what a psychologist can really do. And I think what I learned from that experience, so, you know, in collaboration again, that, yes, I was a psychologist. I'm really good at getting mice to behave. And I think I'm a mouse whisperer in that way.
00:23:37:06 - 00:24:21:02
Denise
But they're right. I don't have engineering background. I don't have optics background. And so working together with someone from a physics background and working with Tristan Shuman, who taught me about CREB and now he is helping us developing the surgeries to be able to do these experiments. And I think this also, you know, when we were first developing this open source technology you know, we didn't invent anything new that the technology was already invented, but we thought how powerful would it be if we could create an open source version of this commercialized miniature microscope that we later called the miniscope, if we could make it open source version that was accessible to anyone in the
00:24:21:02 - 00:24:40:03
Denise
world, and that we can make it for one 100th of the cost of the commercially built. Right. And like we can remove barriers to science now instead of only the richest lab. Now, anyone can ask questions and answer questions about the brain and lead us to insight and interventions and, you know, maybe drug discovery and cure brain disease. Right.
00:24:40:17 - 00:25:09:17
Denise
So that was kind of the original plan. And again, once again, I learned that through these collaboration, everyone everyone has weaknesses but we all come with their strengths together. We can solve big problems. And this technology originally when we first started designing that this project, we're like let's make it so that not only did we, you know, develop the actual hardware, the software, but let's also develop the resource so other people know how to do it in their own lab.
00:25:09:17 - 00:25:33:18
Denise
Right. For really cheap. And when we first started developing it, we thought, okay, like maybe maybe ten labs would be interested in like that would be worth putting in all of the investment in developing this resource that we have a wiki on now so that we'd launch in 2016. And since then there's been over 500 labs around the world that now use this technology that we've developed and over.
00:25:34:00 - 00:26:00:08
Denise
I think now 3000 people are part of our global community that have registered on our wiki and that, you know, now like they help each other. We've also run hands on workshops where we travel across the world and teach people how to do this. And I mean we've taught over, you know, I think a thousand participants in our workshops now and created virtual resources which I think during the pandemic having virtual resources was really important.
00:26:00:20 - 00:26:27:09
Denise
Yes, I think to students our long winded answer to your question of what is the theme of my scientific career? I think the two themes as I'm talking to you now realize is one is never sell yourself short and, you know, believe in yourself. Even when other people say can't do it. And I think the other thing is really team science, and I'm so about science because nothing I do could have been done without having an amazing team.
00:26:27:22 - 00:26:36:05
Denise
And, you know, our motto of the lab is team together, everyone achieves more. And so, yeah, I guess that those are the two themes.
00:26:36:20 - 00:27:30:04
Kelsey
Your journey I find just so emblematic of science, like the scientific process because it is so dependent on collaborate so there's not a single individual that's going to cure a disease that comes from this after it build it up across decades of research typically that will culminate in something that can actually help people in the end. And then just your efforts to make science accessible as well, I think is just so important because that is such a barrier, I think, to discovery is that the access to these materials such as this these miniature microscopes would be if you don't have like an engineering background where access to these things, how it or a ton of funding
00:27:30:15 - 00:27:33:21
Kelsey
how are you going to access that type of technology? So.
00:27:34:05 - 00:28:01:14
Denise
Yeah, I feel very privileged to have been, you know, a part of this amazing team of people that have both the vision, the and the creativity, the generosity and spirit to envision how science would be so much better, how our humanity would be so much better if we did science in an open way in which we share with each other that we can learn from each other and very importantly, how we can innovate on top of, you know, everything we've done in the past together.
00:28:01:22 - 00:28:10:15
Kelsey
Yeah, I think that that's key to scientific progress. It seems almost counterintuitive to approach science in many other perspective.
00:28:10:18 - 00:28:14:23
Denise
I mean, I'm with you. You're preaching to the choir here. Yeah. Yeah.
00:28:15:07 - 00:29:08:01
Kelsey
So, I wanted to ask a question although we kind of spoke about this already, what experiment would you consider to be something that you find represents the scientific experience? So it could be something really annoying, surprising like Pinnacle Moment, but something I think that so often gets overlooked in the scientific process is that the process itself, because especially I think people see it now with the COVID pandemic, the actual process that goes into developing these scientific discoveries.
00:29:08:16 - 00:29:18:05
Kelsey
But otherwise most of the time people just see this end result and they don't actually, you know, see the day to day that goes into that.
00:29:18:07 - 00:29:52:22
Denise
So, yeah. So there are two experiments if it's okay, show two. Yeah. Okay, great. One experiment was, you know, in my, in my graduate experience. And so I would say like the way that I think about science that is natural for me is through my own human experience and coming from the human perspective and something that my advisors, Sara Mednick and I were very interested was in the idea of creativity and where does creativity stem from?
00:29:52:22 - 00:30:11:13
Denise
Right. And there's a lot of antidote to evidence that, you know, that some of the most novel ideas, such as like creating the benzene ring. Right, was the scientist had this dream about the snake that turned into, you know, that formed a circle and that that scientist in all of them was like, oh, I like this is how we solve this problem.
00:30:11:13 - 00:30:37:05
Denise
And then came the benzene ring. And, you know, you and I might have this intuition that it felt like we have these dreams that I have amazing creative associations that lead to creative insight. And so we we thought to test this, and this is something I mentioned earlier that we use as creativity task cognitive systems test. And it tested, you know, novel association between words that were not previously made before.
00:30:37:23 - 00:30:59:15
Denise
And in this study, we had our human subjects come in and do some of this task previously. And then we implicitly gave them some other task with hidden basically hidden solutions to future problems that they would see later. And then they took a nap. And so it half the subjects. We woke them up around 60 minutes so they didn't have to sleep in the other half.
00:30:59:15 - 00:31:22:09
Denise
They got REM sleep. And then we also had like waking controls. And then, you know, when we looked at the data, we found that those subjects that got REM sleep were the ones that were able to use the hidden answers on the solution later better than subjects who did not have sleep and I just couldn't believe it because I was like, Wait, that's what we thought.
00:31:22:09 - 00:31:45:16
Denise
We thought that, you know, this, this stage in sleep that was rich in dreams might help us form associations together and to actually see it come out in a well controlled study, the data was amazing. But I will tell you, even after we published that paper, and it got a good amount of press, I was still not convinced. Maybe it was a fluke.
00:31:45:16 - 00:32:11:21
Denise
Like maybe, you know, and it wasn't really until a number of other people had replicated our data that I was like, okay, I think what we discovered was real, which, you know, took years later for other people to replicate. I think the second set of experiments, which I also alluded to before, so when I was starting my PostDoc and again, the question really comes from my human intuition about memories.
00:32:11:21 - 00:32:29:05
Denise
Right? And this is your actually your intuition that you have, which is that in real world, we have all these memories that happen. And so how do they interact together? How does one form the other? And so we have this intuition that, you know, memories that were formed close in time were somehow more likely to be related, that memories that happen far in time.
00:32:29:05 - 00:32:51:02
Denise
Right. And this idea, intuition that you might have that, like if we think back to, you know, a memory recalling that memory is more likely to trigger than the recall of another memory that happened close in time, compared to further time, given how does the brain do this? Because of my background in studying the hippocampus, which is brain region really important for storing these everyday memories, I was like I want to say in hippocampus.
00:32:51:13 - 00:33:26:21
Denise
And we have this idea that experiences close in time might even though they're very different right let's say an animal explores room A and then hours later they explore room B and our hypothesis was that maybe the representation or the neuron ensembles encode these two memories plus the time have this overlapping ensemble compared to experiences further in time. And everyone said, oh, silly Denise, like that can't be true because decades and decades of research shows that the hippocampus is very good at separating these two rooms and representing that in the brain.
00:33:28:19 - 00:34:15:12
Denise
And and so despite other people saying, Oh, silly Denise, you're so wrong, I was like, well, let's really just test this hypothesis. And, you know, I'm really grateful that my, my post-doc advisor gave us a lot of freedom in the lab. To really test our ideas. And indeed, we found that using this miniature microscope because we can track all the cells were active across all the different experiences right now using this novel tool, we did indeed find that one of the ways my ways are temporally linked is that they are shared overlapping representation such that when animals then recall one memory, they can trigger the recall of a temporally related memory through that neural ensemble that
00:34:15:12 - 00:34:30:13
Denise
shared between the two memories. So I think that that experiment also showed that sometimes you just have to really test it out for yourself. Right? And not listen to the naysayers and find out what the real answer is.
00:34:31:13 - 00:34:40:02
Kelsey
Definitely. I mean, if we just wrote everything off and we already know everything about that, so much discovery would be missed
00:34:40:02 - 00:35:00:04
Denise
Yeah, absolutely. And I think that as I have mentioned to you, like as I was stepping into my Ph.D. and then into my postdoc and even into my faculty position, I always felt under-qualified. Right? I started my PhD like, but I was a pre-law major. Like, I knew nothing about psychology. And then when I started my postdoc, I'm like but I got a PhD in psychology, I knew nothing about the biology.
00:35:00:10 - 00:35:27:16
Denise
And then when we started developing, you know, like neurotechnology and like, I have no engineering background and so I think, you know, stepping into the unknown actually has been really beneficial to me because it one forces me to collaborate with other people and rely on the strengths of so many other people that are way smarter than me. But I think the other thing is that stepping into a new field has really helped me to think outside the box because I don't know what the box is.
00:35:28:04 - 00:35:45:09
Denise
And so while that used to be a big insecurity for me of, you know, people with top us imposter syndrome or feeling like you're not good enough. And now I think about it as my superpower because I don't know the rules and the dogmas, so I don't need to, you know, think within those lines.
00:35:45:09 - 00:36:02:04
Kelsey
Right, right. Yeah. What advice would you give to someone that maybe in the position that you were in back in college where you thought you were on the set path and then ended up diverging completely? Yeah, even throughout grad school, I feel like you.
00:36:02:09 - 00:36:37:14
Denise
Yeah, I think like the the thing I would tell my younger self and this is what I tell people my lab, is dare to fail, dare to dream and to fail, dare to test your ideas and fail. And I think like, you know, you know, here we've shared some of the experiments that kind of worked out, right? But for example, I would say about 80% of the experiments I completed were never published because for one, we said there, you know, my hypothesis was wrong.
00:36:37:14 - 00:36:57:18
Denise
And then we had to now, but then we learned something from that and then we went a different way. And so I would say that scientific discovery or mastery of science is not about success or failure, so to speak, but it is that the learning how to constantly fail, but learn from that and take your next steps. Right.
00:36:58:08 - 00:36:59:08
Denise
So yeah.
00:36:59:17 - 00:37:28:17
Kelsey
Yeah. I feel like so much of science is failure like. Yes, just you're not going to be right with every hypothesis and it can either. I think almost at least for me. And I know people in my graduate program all had the same imposter syndrome you're talking about. And initially the failing experiments can almost get into that until you have to take the perspective that what can they learn from this.
00:37:28:17 - 00:37:53:19
Denise
And yeah, I think when they have the best example and maybe dare to fail is the wrong way to say it. Maybe it is dare to be wrong. Right. Because for example, like, I love this example. So now, right. That the hot Internet game is Wordle. And one of the biggest lessons from this is even when you choose the wrong letters you learn what the word is not right.
00:37:53:19 - 00:38:09:20
Denise
And that helps you get closer to what the word actually is. And, you know, I think that that is so apropos to the scientific discovery. So much of our discovery is not field experiments. It's that we learned that our original idea was wrong.
00:38:10:04 - 00:38:10:11
Kelsey
Right.
00:38:10:12 - 00:38:12:18
Denise
And that is also just as informative.
00:38:13:08 - 00:38:29:03
Kelsey
No, definitely. And it's almost more I mean, I know a lot of people get proud for it when they get on the first try. That's just guess work. Yes, it's almost more impressive. Yes. When you can work through the process of elimination, actually come to the correct answer, which is science.
00:38:29:09 - 00:38:31:03
Denise
Yes. Yes. Actually.
00:38:44:19 - 00:38:55:03
Kelsey
Well, thank you so much for taking the time to talk to me today. Is there anything else you'd like to include for our listeners?
00:38:55:18 - 00:39:14:09
Denise
Yeah, I just want to say, I think the other thing that I really learned from this and that we touched a little bit upon this. Right. And one of the reasons I'm so committed to open science is because I really believe that in order for us to do the most innovative science, we need to bring different people from diverse backgrounds and various perspectives.
00:39:14:21 - 00:39:38:18
Denise
Because if we're asking the same question and answering in the same way, we're never really going to answer to that question. Right. And so I just want to say that what I've learned over the the past many years of being part of scientific discovery is the importance of bringing different perspectives, coming together to solve and to bring a new solution.
00:39:39:07 - 00:39:49:14
Denise
So I want to leave us with that. And I also just want to say thank you use so much Kelsey for creating the space for us. The other speakers, and for listeners and for this opportunity to share.
00:39:50:08 - 00:39:50:21
Kelsey
Thank you.
