IRA FLATOW, HOST:
A recent study has pinpointed key molecules involved in the formation of long-term memories. Scientists at the University of Pennsylvania studied patterns of gene expression in mice to determine how the brain stores information that can be recalled months or even years later.
And the results of the study, the results are part of a growing body of research that looks at how so-called epigenetic mechanisms where the body's way of regulating genes may influence our ability to form memories. Ted Abel is professor of biology at the University of Pennsylvania in Philadelphia. He oversaw the study of mice and long-term memory formation. Welcome to the program.
TED ABEL: Hi, Ira, thanks for having me on today.
FLATOW: What were you looking for for the study on memory? What were you looking for in these mice?
ABEL: So we were looking to identify the key proteins that would store long-term memories in a brain region called the hippocampus, which is the part of the brain that's responsible for memories of places and contexts in rodents, and in humans it's memory for episodes of our lives, for people, places and things.
FLATOW: And how do they - how does memory storage work? What's the ABCs involved here?
ABEL: Well, so the ABCs are that the initial storage of memory, the short-term memory, involves the connections between neurons and the synapses and the activation of neurotransmitter receptors and protein molecules at the synapse.
But very long-term memory for days, weeks, months and years involves the activation of genes in the nucleus and turning on gene expression, reading out DNA into RNA, and that RNA then encodes proteins that go out into the cell and modify the function and structure of neurons.
FLATOW: So something must tell the DNA to make these proteins.
ABEL: Right, so that's the critical process that we studied, and what researchers have found, my lab as well as labs elsewhere at Columbia and at the University of Alabama in Birmingham and at the University of California in San Diego, what they found is that the mechanisms of regulation of gene expression involves the processes of epigenetics, and that's been a very exciting field that has studied how DNA and how the proteins that DNA wraps around the histones are modified to regulate the expression of genes.
And what's exciting about that field is that these biochemical marks, these epigenetic marks, they respond to experience, to neuronal activation, and then they can be long-lasting and change gene expression for days, weeks, months and to mark particular genes in the nucleus so that when we're re-exposed to a stimulus or an event, the gene expression is reactivated, and that memory is reactivated.
FLATOW: Fascinating, so by stimulating the genes, you create the memories.
ABEL: Yes, and so what we did, though, is to try to block the genes and then block the memories, but we are able to stimulate memories by giving drugs, which are called histone deacetylase inhibitors. And these HDAC inhibitors, as they're called, they increase the levels of a particular epigenetic mark, which is called histone acetylation.
And what this study particularly did, Josh Hawk, who at the time was a grad student in my lab, he's now a post-doctoral fellow at Yale University, what he did was to make a mutant mice in a gene that we thought was the target of histone acetylation, and that gene was a transcription factor that regulates gene expression.
FLATOW: All right, we're going to take a break, come back and talk more with Ted Abel about this work with the mice. So stay with us. We'll be right back after this break. I'm Ira Flatow. This is SCIENCE FRIDAY from NPR.
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FLATOW: This is SCIENCE FRIDAY. I'm Ira Flatow. We're talking this hour about how long-term memories are stored in the brain. My guest is Ted Abel, professor of biology at the University of Pennsylvania in Philadelphia.
And so just to sum up from where we left off, you're saying that when we want to remember something, we stimulate part of our genes in our brains, and that stimulates our brain to create proteins that store the memory. Would that be correct?
ABEL: Yes, that's correct, and that process is regulated at each of the steps, and I think what's exciting firstly beyond understanding the molecular working of how something as complex as memory would function, we also can identify drugs that can particularly modify each stage of the process and hopefully treat the kinds of cognitive deficits that accompany disorders like Alzheimer's disease or schizophrenia.
FLATOW: Would these drugs stimulate you to create new memories or block the loss of the memories?
ABEL: So in this case - that's a good question. One can think about doing them both ways. You can think about modulating memories in each way. And what the drugs we're talking about would probably act to enhance the formation of new memories. That's certainly what they do in mice when we study them.
FLATOW: And you found - and you've identified the genes that do this?
ABEL: Yes, and so that's what's exciting about this is that we think we have the, you know, beginnings of the molecular circuitry for how this goes into - how this is all set into motion. And the challenge now is to really identify - what we've done is identified a process within the nucleus, the part of the cell where the DNA is stored that sets this process in motion.
The challenge is to identify really how these factors in the nucleus, what their target genes are that then are affecter genes that come - code proteins that come out to the synapse to change the function there. We think we have some ideas of that, and we discuss that in this study, but they involve these genes that are called neurotrophic factors, what's called brain-derived neurotrophic factor of BDNF and that that is regulated by this process, these epigenetic processes and then can go and modify synapses.
But we need to do future experiments to really show that that's functionally the case.
FLATOW: I should say this study is part of a relatively new era and area of research known as epigenetics, which looks at, among other things, how the regulation of genes influences memory. David Sweatt is chair of the Department of Neurobiology at the University of Alabama at Birmingham, and he's also studying epigenetics. Welcome to SCIENCE FRIDAY.
DAVID SWEATT: Hi, Ira, thanks for having me on.
FLATOW: Did you ever think - I mean, did people believe that genes could regulate memory?
SWEATT: Certainly, it's been one of the most exciting developments in the last couple of decades in the whole memory field. It is a paradigm shift, though, from the kind of old style of thinking. You know, we're kind of used to thinking about genes and environment, you know, nature versus nurture and that old debate.
And what these kinds of studies are making very clear now is that's really a false dichotomy, that there's a constant interplay between your experiences, your sensory inputs and the genes in your brain. And that part of how you learn and remember is your experiences dynamically regulate the output of the genes in your brain in order for you to be able to store information.
FLATOW: 1-800-989-8255 is our number if you'd like to talk about this. Also you can tweet us @scifri, @-S-C-I-F-R-I. This is something called epigenetics, right? What are we - can you define that for us, because it sounds very interesting.
SWEATT: Yeah, I'll take a stab at it. All those scientists, like everything, argue about what the precise definition is. But there's - we know that there are genes, and that's a unit of information storage that's encoded in your DNA, and people are very familiar with that.
But there's another layer of regulatory mechanisms that sit above the layer of the genes, so epigenetic mechanisms. And these are information storage mechanisms, as well, that operate in a different fashion that the information storage in the gene, but they're mechanisms that are extremely potent regulators of gene output, so readout of the gene products from the DNA.
And so these epigenetic mechanisms are, kind of, master regulatory mechanisms that control gene readout. And part of the discoveries in this area have been that these epigenetic regulatory mechanisms are how, part of how your experiences get translated into alterations in gene output that allow you to lay down new memories.
FLATOW: So you're not - you're not saying that the genes themselves are changed?
SWEATT: No, no, it's the - it's these regulatory mechanisms that sit above the layer of the gene that are controlling the extent to which that particular gene product is read out and made in the cell.
FLATOW: So any change that's made there, is that passed on to the next generation?
SWEATT: It's theoretically possible, and there's a little bit of data that certain types of acquired attributes like that can be heritable, but that's a very rare phenomenon. And it's certainly not something that is going to be the way that people might typically think about, you know, remembering something that -an experience that your grandmother had or something like that. It's not going to operate at that level.
FLATOW: So this sort of explains a chemical or neuronal basis of the nature versus nurture question.
SWEATT: Exactly. It's the epigenetic mechanisms - and I'm being a little hyperbolic here, but, you know, that's the interface between nature and nurture. That's the mechanism that evolution has put in place to allow those two things to dynamically interact with each other.
FLATOW: And Dave - Ted Abel, how did this paradigm shift influence your approach to studying memory?
ABEL: Hi, Dave, how are you doing? It's great to speak with you over the distances here. It's - so I think it's really had a dramatic influence on how we think about memory and really how the field thinks about memory because firstly it's provided, as Dave said, the connection between experience and the neuron. And it's really given us a set of biochemical mechanisms that really are the critical switches for how memories are stored.
But what's interesting about them is it's not just the biochemical switches, they're also storage mechanisms. So, you know, Ira, you mentioned that these could be, in some cases, heritable; and that's true in other systems and I think not probably true from these behavioral experiences, or researchers are still studying that.
But what's important about these is that they're long-lasting and that there's this complex code of modifications. I mentioned histone acetylation, but there's a number of these epigenetic modifications. And it could be that these modifications form a biochemical code that could actually be the storage of memory, could be information storage.
And that would be - we haven't really - we haven't shown that directly yet, but that would be the sort of real revolution that you could store memories in your nucleus and that it's these biochemical tags that could be that information.
FLATOW: Let's go to the phones, 1-800-989-8255. I have Dr. Kenneth Fish(ph) from Gaithersburg, Maryland. Hi.
KENNETH FISH: Hi, I was educated, apparently, before dirt, so I need to get an update. My understanding of the way memory works is more holographic, that it's the function of major organs in the brain, the hippocampus, the thalamus, the transfer of information, globally, throughout the brain.
And my question is: Is there some way to relate that to what we're talking about here, which is at the very micro-structure and its effects on the macro-structure?
FLATOW: Ted, David, who would like to take a whack at that?
SWEATT: Go ahead, Ted.
ABEL: Go ahead, David.
SWEATT: I'll take a whack at it. Yeah, the kind of systems neurobiology I think is what you're referring to, is certainly the case, where there is, you know, constant interactions between various brain regions that allow us to cogitate, basically, and learn and remember in that fashion.
Ted and I are operating - I mean, we study learning and memory in behaving animals in the laboratory, but we're really trying to understand things at a much more minute molecular and cellular level. And it's clear that those types of mechanisms contribute, as well.
And then there's a big black box between, kind of, the molecular level and the cognitive level in terms of how the interplay between the molecules and the systems contributes to learning and memory, and it's - you know, most of that is mysterious at this point.
ABEL: You know, maybe if I could just chime in, as well. The one - sort of two comments. I think the first comment is that what's clear at the systems level is that there are distinct memory systems. So there - I mentioned this earlier that there are some memory systems for our episodic memory, which is mediated by the hippocampus. There's memory systems for more emotional memories, which are mediated by another brain region called the amygdala. There's more procedural and motor memories in the striatum and cerebellum. So you have this kind of partitioning of memory in general, and then within each of these brain regions, like the hippocampus, Dave is right, that really the interface of how you then get down to the molecules and come back up to systems is really one of the major challenges.
But one way that - one thing that's quite interesting is that researchers, in particular Mark Mayford has done experiments like this in California, and he studied the activation of genes in particular sets of cells in the hippocampus. And you can argue, and another researcher Carol Barnes has studied similar kinds of problems, that each experience might turn on a gene in a set of neurons. And then there's another experience that would turn on genes in another set of neurons.
And it's that constellation of neurons for experience A that is that - involved in that memory, and another constellation of neurons for experience B that are involved in that memory. But within those constellation of neurons A and B for the two different experiences, the molecular events may be similar, but they're wired in such a way that they're activated more readily by one particular experience than another. So that would begin to get to your kind of holographic idea in a sense. But I would see it as the lighting up of gene expression in a set of neurons potentially as being the circuitry that would mediate that memory.
FLATOW: And it's the whole integration of it together that creates consciousness or thought, things like that.
ABEL: That's right.
FLATOW: Yeah. Let's go to a - let's get to the phones. So let's go to Melissa(ph) in Boise. Hi, Melissa.
MELISSA: Hi. Thank you so much for taking my call.
FLATOW: We enjoyed our stay in Boise. Thank you for being such a good host.
MELISSA: Oh, I'm glad. It's cold now. So it may not be as pleasant.
MELISSA: I was calling - I'm curious to know, what could this mean for patients that are suffering from Alzheimer's? Does this help with the creation of new memories, or could this actually help with the retrieval of, well, previously forgotten memories in their case?
SWEATT: This is David. I think I'll comment on that, and, of course, would love to hear Ted's thoughts as well. But that's one of the things that a lot of us are working - who work in this area are really very serious about, trying to translate these discoveries about the basic neurobiology of learning and memory into new treatments. The - we've done some studies with genetically engineered mouse models of Alzheimer's disease and have found that these histone deacetylase inhibitors that Ted and our group and others have been looking at in these mouse models can help restore the animals' capacity for learning when it has Alzheimer's-like dysfunction, memory dysfunction.
So in the studies that we and most other people have done so far these histone deacetylase inhibitors take an animal that has a learning and memory deficit, so it's unable to store new memories, and restores its function so that it can apparently store those new memories normally. So if that hopefully translates into the human condition, then it would alleviate some of the problems that we see with Alzheimer's patients in terms of them being able to - unable to recall recent events and events over the last couple of days, for example.
FLATOW: This is SCIENCE FRIDAY from NPR. I'm Ira Flatow. Do these involve drugs that have to be developed? Or are they compounds we already know about and could be tested?
SWEATT: There are compounds that we can use in animals in the laboratory that are not really safe to use in humans to be frank about it at this point. It's a very robust area of drug development right now, though. There are a couple of problems with the drugs we have. They don't get into the brain very well, the ones that we have right now. And they have selectivity issues, that is they're not as selective for one versus another type of enzyme that may be involved. And so a number of biotech companies, pharmaceuticals, these are developing HDAC inhibitors that are alleviating or trying to alleviate some of these problems.
ABEL: What's exciting about - one thing that's exciting about the drugs is that in animal studies at least they can be given after animals have began to show memory loss and have began to even show some neuronal loss. So the really encouraging thing from the animal studies on the clinical side is that the drugs have the promise of being able to treat patients, you know, in - that are into the really - into the disorder, and they don't have to treat them sort of before it occurs.
The other thing that's kind of interesting is that we're finding that some other drugs, one example is folic acid, that have been around and used for other targets and other disorders, for example, for epilepsy with that drug that they have an activity that changes histone acetylation, and it's partially an HDAC inhibitor. So the other avenue is to look at existing drugs and to see what, you know, in what ways they change these epigenetic marks and if that might actually be the mechanism that they work and that we haven't previously identified that.
FLATOW: What do these drugs do for all the plaques and entanglements and things like that we see in Alzheimer's? Do they even mention those things? Or if they're going to restore memory in some of these mice, I mean, are they working in that mechanism or a totally different mechanism?
SWEATT: It looks like it's a different mechanism from that. That is the kind of traditional neuropathological...
SWEATT: ...markers are not affected by these drugs, at least in the kind of shorter-term studies that have been largely done so far.
ABEL: And maybe that they - that these drugs would support the kind of resilience of neurons to that insult of having these deposits. But most of the studies, as David pointed out, have been relatively short term in animals.
FLATOW: So we're looking about - no one should think that we have something new around the corner here?
SWEATT: No. That's for sure. But it is - like I said, it is a very active area of development. Ira, I would like to make kind of a comment on this as well because it's relevant to this exciting paper that Ted just published, Ted and Josh. It's been well established for a number of years now that these HDAC inhibitors are very powerful enhancers of memory formation in laboratory animals. But it's been completely a black box as to how it is that they work. It's quite a striking phenomenon that they can affect memory capacity in the behaving animal. But we really had very little insight into what the underlying mechanisms, biochemical infrastructure was.
And I think Josh and Ted, with this new paper they published, have kind of cracked open the lid on that box, so to speak, and given us really the first insight into what the molecular sequence of events maybe that's being triggered by these HDAC inhibiters. And, of course, the better that we can understand that, the better we're going to be able to refine the drug development, and that's one of the things that's really quite exciting about Ted and Josh's new paper.
FLATOW: Good way to wrap it up. Thank you very much. David Sweatt is chair of the Department of Neurobiology, University of Alabama at Birmingham. Ted Abel, professor of biology at the University of Pennsylvania in Philadelphia. Good luck with you, gentlemen.
SWEATT: Thank you, Ira.
ABEL: Thanks, Ira. Thank you.
FLATOW: Thanks for taking time to be with us.
ABEL: Good to speak with you. Bye.
FLATOW: We'll be right back after this short break, so stay with us. I'm Ira Flatow. This is SCIENCE FRIDAY from NPR. Transcript provided by NPR, Copyright NPR.