Jonah: I’m Jonah Chester.

Clay: I’m Clay Catlin, and you’re listening to Animal/Human.

Jonah: This show is a production of IU’s College of Arts and Sciences and a proud part of the 2018 Themester.Clay: Each episode, we talk with a different IU researcher to examine where we,as humans, belong in the animal kingdom.

Jonah: We also examine the interactions of humans and animals in art, literature and science. In this episode, Clay sits down with Dr. Jonathan Crystal. Dr.Crystal works as a part of IU’s Department of Psychological and Brain Sciences.

Clay: Dr.Crystal looks at how animals perceive and remember the world around them. Specifically, how their sense of memory is affected by degenerative neurological disorders, like dementia and Alzheimer’s.

Jonah: He hopes to use these insights into animal cognition in order to better understand exactly how these diseases affect humans. Using this information, he believes he can help create therapies to help mitigate the impacts of illnesses like Alzheimer’s.

Clay: Hello thank you for coming onto the podcast.

Dr. Crystal: It’s a pleasure to talk to you.

Clay: Alright, so my first question is: can you tell me about your work at the Comparative Cognition Lab at IU?

Dr. Crystal: So research in my lab focuses on developing animal models of memory. We’re particularly interested in the type of memory that's impaired in human diseases. So the big disease is Alzheimer's disease and the big impairment in memory in Alzheimer's disease is a real lack of what people call episodic memory. So episodic memory is your memory for personal past experiences that happen to you. So for example someone who is talking with their grandmother who is suffering from Alzheimer's disease she won't remember that there was a visit say two weeks ago and the all things that were described about what’s going on in one’s life and that's really very distressing for everyone involved.

Clay: In your work what is one sort of surprising way that humans and animals, specifically rats because that's what your work focuses on, what is a surprising way that they alike?

Dr. Crystal: Right so if I had to say what's similar about rats and people, it's probably not their memory. It's the love for chocolate. Rats love chocolate. There's really no amount of chocolate you can give a rat that’ll stop it from eating chocolate, we’ve tried. So, why would you try to get a rat to stop eating chocolate? So this goes back to episodic memory. One of the main definitions of episodic memory focuses on remembering what people call what, where, and when. So, what happened to you? Where were you? When did it occur? And so in experiments where we showed that rats have an integrated representation of what, where, and when, we wanted to know if they really knew what the event was. And in our experiments, in these types of experiments, we used different flavors of food.

So I mentioned rats love chocolate, we give them a special location that gives them chocolate and gives them more chocolate at a later point and, to show that they really remembered the specific content of that event, we devalue a flavor. So, if you try to devalue with chocolate it's really ineffective, if you use other flavors that they like, like grape and raspberry, then you can devalue a flavor. So this would be very much like what people experience and what people call “flavor specific satiety.” So if I gave you a lot of potato chips and gave you a choice between pretzels and potato chips you would take the pretzels and the rats do the same thing except when it's chocolate.

Clay: Interesting, so is there any idea of what about the chocolate is so irresistible to the rats?

Dr. Crystal: It’s chocolate!

Clay: Okay! Good point, how are the ways that animals encode and retrieve memories different than the ways that we encode and retrieve memories or similar?

Dr. Crystal: Right, so if I wanted to assess your episodic memory it would be really easy. I’d ask you about things that happened to you and you would tell me and I’d believe you. So unfortunately we can’t do that with nonverbal animals so instead we have to train them with experiments that give an opportunity to learn the rules of an experiment and then we can assess their memory. So, I’ll give you an example and again this is one that focuses on one of the ways that we try to establish episodic memory in rats. So before I mentioned that one of the popular ways to assess episodic memory is to inquire if the animals remember what, where and when and one problem with that is to get the animals to show us that they remember what, where, and when we have to train them. We train them over and over and over again. And after we’ve trained the animals it's always possible that instead of retrieving their episodic memory that instead they’re just using some other type of memory. That would be real threat to the validity of any model that's claiming episodic memory.

So a common example of that would be like if I asked the person who I just hired to work in my lab what did she have for breakfast. The first time I ask her that she’d say, well maybe she’d say, “I was in my kitchen and I had toast and orange juice.” But, now imagine that every time I see her I ask this weird question, what did you have for breakfast? Now the second time I ask she’ll think, “he's a little strange, he wants to know again what I had for breakfast. Today maybe I was at Starbucks and I had coffee and a scone.”

The problem is, eventually, if I keep doing this over and over and over again she's going to be sitting in her kitchen one day and saying, “cereal and coffee,” because when she sees me that's the thing she’s going to say. And of course with people we don't have any reason to be suspicious or doubtful that we really remember our episodic memories. But if you could just carry forward that answer and when you see me say, what was it “cereal and coffee,” you’d be getting the answer right, but you wouldn’t necessarily need to be traveling back in time to retrieve the episode that happened to you. So this is a problem in pretty much all experiments with nonhuman animals, we train them over and over, and they can learn to expect all the things that they’ve had in the past continue to happen again in the future. They could get the answer right, which looks encouraging to us, but without actually remembering the episode.

So this gets to your question, how do we solve that? We need to come up with some approach that allows the animal to communicate its answer via its behavior to answer a question that we can then arrange that it's the very first time they had that question, and they had no reason to believe the information that they need later would actually be needed. So people call this “incidental encoding” and “unexpected questions.” This would be like I came into the building today if this was the first time I came into this building you might ask me, “what did the doors look like?” Again, one of these bizarre questions and I don't know maybe I didn't pay attention to the doors when I walked through them, and I can’t answer that. But if I can, we could be reasonably certain that I used episodic memory to get that answer. Because at the time that I walk through the doors there’d be no way to know that that incidental information, that the doors are made out of wood, that they were really tall, that they have glass panels, or what have you -- there's no expectation that you're going to be asked a question like that. And that information in that moment is incidental, it's of no great importance.

So how do we do this with non-human animals? So in one of our experiments that showed that rats encode information incidentally and that they answer unexpected questions using episodic memory, we trained them to report via their behavior: did they just have food or no food? That's an arbitrary rule, you have to train the animals. But after they’ve been trained you can then use that reporting skill in a novel situation where they are searching around for food, they're foraging, and they find food, and then they can use this reporting skill by making a turn in one direction or another to report that they had food or no food.

Clay: Oh, so that's how the reporting works, its based on turning?

Dr. Crystal: Yeah, so we train them with a rather arbitrary rule that if they get food to run down a runway and make a left-hand turn. If they get no food, run down a runway and make a right-hand turn. That arrangement is counterbalanced across the animals so that the other animals have the opposite arrangement. And then we just let the animals forage. This is something that rats naturally do, we don’t need to train them. They search for food. When they find the food, they move on to other places. And so if you have to say what's the important thing while they’re foraging its did they get food or no food. As I say, we don’t have to train them so an example I like is: this is what rats are doing behind my favorite restaurants on fourth street every night. They’re finding the food, I’ll say outside the restaurant, and they're eating the food and then they’re moving down the street to your favorite restaurant and they they’re finding the food there, and then they move on to yet another place.

So finding food is the name of the game and at any point we can interrupt them and ask them, “did you just have food, yes or no?” And we did that in a couple of experiments, in one we gave them food while they were foraging which is a good deal for them, and they reported correctly that they had food. We gave them the unusual situation in which they’re searching for food—they’re foraging— but they’re not finding any food and now they should make the opposite turning response. Because episodic memory requires and intact hippocampus we next surgically implanted the animals with stainless steel cannula, we temporarily inactivated a part of the hippocampus using lidocaine and that took animals that previously were shown to be able to answer this unexpected question after incidental coding and it completely wiped out their ability to do so. They were still able to do other behaviors like the left turn and the right turn and that was intact, that doesn't require memory of the episode. But if you give them an incidental encoded event and then ask them to report do they remember the event you need a functioning hippocampus.

Clay: So this procedure you did inhibited their episodic memory?

Dr. Crystal: Inactivating the hippocampus wiped out episodic memory.

Clay: Interesting, and is the hippocampus, is that a part of the brain that works similar in humans to rats where it stores the episodic memory?

Dr. Crystal: Right, so there's a lot of evidence from neuroimaging studies that the hippocampus is a critical processing center for episodic memory in people.

Clay: How do you train them to make these sorts of movements whether they’ve had food or not?

Dr. Crystal: Yeah, so that takes a lot of training. It's not a natural thing for the animals. We have to train them in this arbitrary rule, its quite different than the foraging game which the animals pretty much come to us being able to forage, but we give them a reward if they make the correct choice and we give them no reward if they make the incorrect choice and with enough experience they readily learn these arbitrary rules.

Clay: Interesting, how is disordered cognition present in animals similar or dissimilar to the disordered cognition, like Alzheimer’s, that is seen in humans?

Dr. Crystal: Right, so I mentioned that we’re really interested in episodic memory because it is profoundly impaired in Alzheimer's disease. It's the most debilitating aspect of Alzheimer's disease and one of the problems with research that's being done to develop drugs for treating Alzheimer's is that almost all of that work uses genetic models of Alzheimer's disease in mice. And, you were asking a moment ago about how we train the animals to learn these arbitrary rules. Well, it turns out it's a lot easier to train animals when they’re rats for those types of experiments than for mice. So here's a problem, almost all the work that's done with these genetic models were developed in mice because the mice are small and cheap and they breed quickly, so it was the sensible way to develop these genetic tools, these genetic models of Alzheimer’s disease. But almost all of the assessments of their memory in mice involves what I’ll call an assessment of spatial memory, that's like finding the food behind a restaurant. There’s nothing wrong with using spatial memory the problem is that if you are using it to try to develop a drug that treats the symptoms of Alzheimer’s disease that would be like having a drug development program that you spend many years and hundreds of millions of dollars and it helps you find where you put your novel or where you put your glasses or your car keys. Although it would be nice to get some improvements in those aspects of memory, its very likely that that will fail to translate to episodic memory.

So this is a problem; almost all the models historically have developed using mouse genetics. Fortunately, increasingly these models are being developed in rats, so gene editing technology has become cheap and fast and, so increasingly, there are Alzheimer’s model rats that can be used to test for potential therapies.

Clay: So have you worked with both mice and rats?

Dr. Crystal: Yeah, we’ve done some work with mice, and it largely led us to go back and do our work with rats. So this goes back to what I was saying, mice are not little rats, and it's very hard to get them to do the things that we can get the rats to do.

Clay: And is that something that you're doing specifically in your lab to study disordered cognition, using rats over mice or is that just the general trend?

Dr. Crystal: So I think a lot of people have made the same discovery that it's hard to get mice to learn the things that you can get rats to do. The developments that we’ve done to produce these models of episodic memory were done in rats and the new availability of Alzheimer’s genetic models in rats opens up lots of opportunities that weren’t available just a handful of years ago.

Clay: So I know you’ve talked about this a few times, but what is you think one of the biggest obstacles you’ve had to face studying animal disordered cognition in rat?

Dr. Crystal: Yeah so I would emphasize the distinction between basic science research and more applied research. So, the work that we're doing now that's on the applied side is using these Alzheimer’s model rats—combining it with the developments we have on how to assess episodic memory—and we’re hoping to show that as the animals age and develop the markers of neuropathology that are typical of Alzheimer’s disease that they also show impairments in their episodic memory. If we can show that opens up lots of opportunities to use these Alzheimer’s model rats and these methods of assessing episodic memory to test novel therapies for Alzheimer’s disease. So, that's on the applied side but you can’t do the applied research without the basic research that comes before and this is a big problem for lots of fields of science, that the emphasis is on the applied side and its exciting and its great but if you don’t know how to assess episodic memory like in my example then you can’t ask those applied questions. So, we spent quite a lot of years doing the basic science research to develop these methods in rats and are now applying it on this more applied side.

And, when I mentioned that people have a hard time getting the more sophisticated assessments of memory in mice that doesn't necessarily stop people from making claims that the mice are doing episodic memory. So, you could find people who have published papers where they’ve put it in the titles and put it in the abstracts and then you go and read, expecting to see something that looks like episodic memory, and its very likely to be spatial memory.

Clay: Oh, interesting. So my last question is: you obviously spend a lot of time with rats, that's the main thing you’ve worked with as we’ve been talking about and you clearly have a much much deeper understanding of rats than the average person would. These are animals that by most people are considered to be unintelligent, unpleasant, pretty terrifying to some people or pests to other people. But what—through your work with rats—what would you say based on your understanding that you’ve gotten people should keep in mind when they think of rats to get a more sympathetic picture of these animals that are pretty vilified by people?

Dr. Crystal: I’ll emphasize the role of preclinical research, right? So the type of studies that I’ve been talking about people call that preclinical research. Any time you’re taking a drug that's been prescribed to you, long before they’ve ever tested it in people it was tested using animals. So, it's critically important to develop all of this work using nonhuman animals because that's the gateway to testing the drugs in people.

You know, another side to the question that I think I’ll emphasize focuses on the evolution of cognition, so there are a lot of ideas about the uniqueness of people. Humans are very unique, and this sort of relates to the Themester theme of  "Human/Animal."  So, we have all these views that cognition and sophisticated aspects of cognition are unique in people, which may or may not be true for certain aspects, but the only way to evaluate it empirically is to test, in this case cognition, in nonhuman animals. So, we’re really trying to push the envelope on what are the types of sophisticated aspects of cognition that we can assess in nonhuman animals and in all case, episodic memory is the one that I’ve talked about but we’ve done this in lots of different domains, they are domains that people previously thought only people would engage in these types of cognitive processes. And, if you only look in people you’re going to be really impressed with people, and the way to know if it's unique in humans is to test it using nonhuman animals. So that's a really important role for animals in research quite apart of the applied preclinical research that I emphasized a moment ago.

Clay: Right, so our understanding of ourselves in large ways is because of maybe, the rats that have came before us?

Dr. Crystal: I agree.

Clay: Well thank you so much for coming to talk to me!

Dr. Crystal: Thanks a lot, really enjoyed it.

Jonah: This show has been a project of the Indiana University College of Arts and Science Themester.

Clay: As always, thanks to our guest today, Dr. Crystal.

Jonah: Editing, hosting, and mixing for this episode was provided by Clay.

Clay: On the next episode, Jonah interviews Dr. David Wasserman of theAnthropology department.

Jonah: Together we’ll discuss what primates like to eat-and how that influenceshow they evolve.

Clay: Dr. Wasserman believes that the phrase “You are what you eat” is more fact than fiction. They’ll talk about how humans have, over the years, had a negative impact on the environments that we share with animals.

Jonah: Thanks for listening, and we’ll see you next time.