WEBVTT 00:00:03.517 --> 00:00:10.517 This is the Convergent Science Network podcast. Leading researchers in the domain 00:00:10.517 --> 00:00:16.737 of neuroscience, brain theory and technology are interviewed by Paul Verschure and Tony Prescott. 00:00:18.137 --> 00:00:25.337 All right. It's Paul Verschure with Tony Prescott here for the Convergent Science Network podcast. 00:00:25.337 --> 00:00:33.197 And we're here with Daniela Stolzenberg, who was one of the speakers at our school, BCBT school. 00:00:33.737 --> 00:00:37.897 And you focus very much on maternal behaviors. 00:00:38.717 --> 00:00:43.357 Yes. So why do you think that that's an interesting paradigm to look at? 00:00:44.317 --> 00:00:50.837 Well, I started my work in maternal behavior because I was really interested 00:00:50.837 --> 00:00:54.337 in how the brain regulates behavior, social behavior. 00:00:54.337 --> 00:00:59.357 But I find that maternal behavior is particularly fascinating because there's 00:00:59.357 --> 00:01:06.197 such a dramatic change in responsiveness for most mammalian females around the time of birth. 00:01:06.377 --> 00:01:10.577 And so I think it's a question that's interesting on several levels. 00:01:10.717 --> 00:01:14.477 There's a motivational component, there's a learning component as I spoke about 00:01:14.477 --> 00:01:22.397 today, and I think it's a pro-social behavior. So I think you're sort of looking 00:01:22.397 --> 00:01:24.957 at multiple different aspects of social behavior. 00:01:25.197 --> 00:01:31.597 And obviously it's extremely robust and defining characteristic of mammalian behavior. 00:01:31.797 --> 00:01:37.797 But now the framework you took to look at this is what you call epigenetic, right? 00:01:38.417 --> 00:01:39.637 So what do you mean with that? 00:01:40.397 --> 00:01:47.937 So my interest in epigenetics is really in trying to understand how these initial 00:01:47.937 --> 00:01:53.157 experiences with infants lead to long-lasting changes in the behavior of the mother. 00:01:53.297 --> 00:02:00.217 And so I see it as sort of an initial experience that can program this memory 00:02:00.217 --> 00:02:08.237 and really maintain differences in how neurons are functioning in response to infant stimuli. 00:02:08.517 --> 00:02:16.497 And so in that sense, these epigenetic changes that I'm interested in have to 00:02:16.497 --> 00:02:19.857 do with sort of an altering of the phenotype of the neuron, 00:02:20.717 --> 00:02:23.557 within the circuit that regulates maternal behavior. 00:02:24.894 --> 00:02:29.594 So the work is pointing in two directions here. So one is understanding maternal 00:02:29.594 --> 00:02:32.294 behavior in mammals and its origins. 00:02:32.434 --> 00:02:38.594 And the other is understanding epigenesis in animal development more broadly. 00:02:38.974 --> 00:02:42.634 And in your talk, I got the impression 00:02:42.634 --> 00:02:46.474 that there are exciting new developments in both of these topics. 00:02:46.994 --> 00:02:54.354 Yes. So, I mean, if we go with the epigenesis one, so can you just define for 00:02:54.354 --> 00:02:58.154 us more clearly what's the difference between genetics and epigenesis? 00:02:58.634 --> 00:03:01.934 Sure. I think about it really on a molecular level. 00:03:02.054 --> 00:03:06.774 So when I think about epigenetics, I'm thinking about alterations in gene expression 00:03:06.774 --> 00:03:10.754 that are not associated with changes in DNA sequence. 00:03:11.354 --> 00:03:16.134 And so for me, the most straightforward difference between genetics and epigenetics is 00:03:16.474 --> 00:03:22.394 is this sort of molecular distinction, the distinction between alterations that 00:03:22.394 --> 00:03:25.654 are not coded within the DNA sequence, 00:03:25.894 --> 00:03:31.754 but that are affecting when and how genes are transcribed versus the actual, 00:03:31.854 --> 00:03:33.574 a gene or a gene mutation. 00:03:34.694 --> 00:03:38.374 And so, for example, I could give you an example. 00:03:39.974 --> 00:03:43.914 Within the context of maternal behavior, one of the things that we know is that 00:03:43.914 --> 00:03:49.674 is that dopamine neural systems are important for the display of maternal behavior. 00:03:50.154 --> 00:03:55.794 So if we took a genetic standpoint, we could look at mutations in the dopamine 00:03:55.794 --> 00:04:00.534 gene, dopamine receptor genes, and see how that influences maternal behavior. 00:04:01.334 --> 00:04:06.054 If we took an epigenetic standpoint, we might say that some sort of experience, 00:04:06.594 --> 00:04:11.254 might upregulate dopamine receptors for long periods of time or up-regulate 00:04:11.254 --> 00:04:17.854 the dopamine gene for long periods of time, but there's no actual mutation or 00:04:17.854 --> 00:04:19.714 alteration in the sequence of the gene. 00:04:20.274 --> 00:04:24.954 Does that... It does make sense, but I'm still trying to get the difference 00:04:24.954 --> 00:04:28.534 between epigenetics and development. 00:04:28.954 --> 00:04:35.574 When is an aspect of development epigenetic rather than just developmental? I... 00:04:37.398 --> 00:04:42.358 Again, I sort of always go back to this idea that it's a molecular difference. 00:04:42.618 --> 00:04:50.618 And so when an aspect of development is epigenetic, it really has to do with 00:04:50.618 --> 00:04:56.638 alterations to either the histone proteins or methyl marks that are on the DNA. 00:04:56.998 --> 00:05:02.078 So you're taking a very literal, it's got an impact on the DNA inside the cell 00:05:02.078 --> 00:05:04.538 in some way, and then it's epigenetic. 00:05:04.538 --> 00:05:07.478 Whereas a developmental change which for instance 00:05:07.478 --> 00:05:10.578 involved uh i don't know uh alterations to 00:05:10.578 --> 00:05:16.718 the strength of some synapses it's not epigenetic well it it could be depending 00:05:16.718 --> 00:05:20.758 upon what the mechanism is so i think i'm taking sort of a mechanistic definition 00:05:20.758 --> 00:05:24.418 and that's how i think about it um is from this sort of mechanistic approach 00:05:24.418 --> 00:05:29.178 um and so uh so you know again when 00:05:29.318 --> 00:05:33.938 I think about epigenetics and thinking about these mechanisms that drive changes 00:05:33.938 --> 00:05:38.298 in gene expression that can be influenced by the environment. 00:05:38.778 --> 00:05:43.498 So, and I talked about that a little bit today in terms of neural activity can drive these changes. 00:05:44.418 --> 00:05:49.478 But there's, I think, a certain amount of epigenetic mechanisms that are involved 00:05:49.478 --> 00:05:51.278 in sort of the naturally developing organism. 00:05:51.638 --> 00:05:56.518 And I think it's sort of convenient that activity dependent changes can modify 00:05:56.518 --> 00:05:59.238 these processes that are occurring naturally. 00:05:59.758 --> 00:06:04.358 And in the theme of our week, which is evolution and development or evo-devo, 00:06:04.578 --> 00:06:11.318 what's interesting about these epigenetic processes is that they can be passed 00:06:11.318 --> 00:06:14.078 down through the generations. They can be selected for. 00:06:14.458 --> 00:06:20.038 And you think that's the case. In your talk, you made a clear case as to why 00:06:20.038 --> 00:06:23.998 that might be true of kind of maternal behavior in mammals. 00:06:24.818 --> 00:06:29.058 Yes. But what was it that led you to the suspicion that we could analyze maternal 00:06:29.058 --> 00:06:30.958 behavior from an epigenetic approach? 00:06:32.447 --> 00:06:38.907 I think in terms of maternal behavior, I think that it really comes down to 00:06:38.907 --> 00:06:40.827 thinking about it as a learning and memory question. 00:06:41.587 --> 00:06:48.287 And when you think about learning and memory, there's a couple of sort of known 00:06:48.287 --> 00:06:52.567 mechanisms that underlie the consolidation of learning. 00:06:52.727 --> 00:06:58.287 And so one of these has to do with new protein synthesis, the turning on of genes. 00:06:59.067 --> 00:07:04.527 And those processes are sometimes regulated by CREB. 00:07:05.067 --> 00:07:10.367 And CREB recruits a CREB-binding protein, which is a histone acetyltransferase. 00:07:10.507 --> 00:07:16.147 And so the question of how these new proteins become synthesized, 00:07:16.167 --> 00:07:19.767 how these genes get turned on, and whether or not that process lasts for a long 00:07:19.767 --> 00:07:24.967 time, and how that plays a role in the consolidation of learning and the maintenance of memories, 00:07:25.187 --> 00:07:30.547 those things are being explored from an epigenetic perspective. 00:07:30.547 --> 00:07:33.547 Perspective, and I've always been very interested in learning and memory. 00:07:33.687 --> 00:07:39.007 And so I spent a lot of time reading about these things, and I had never thought 00:07:39.007 --> 00:07:43.087 about epigenetics from that standpoint before, but it's sort of like a cellular memory, really. 00:07:43.787 --> 00:07:47.767 And when I thought about it in that context, and I thought about my own research 00:07:47.767 --> 00:07:53.107 having to do with the same sort of question, really, which is this experience 00:07:53.107 --> 00:07:58.667 that's driving this behavioral change that lasts for a long period of time. It seemed that um. 00:07:59.805 --> 00:08:03.785 There might be an epigenetic mechanism underlying it. So the clue, 00:08:03.985 --> 00:08:07.745 or one of the clues for why it might be epigenetic rather than some other form 00:08:07.745 --> 00:08:13.965 of learning and memory was that, I guess, it happens in mammalian species, 00:08:14.785 --> 00:08:16.445 all different mammalian species. 00:08:16.745 --> 00:08:22.285 It happens, I guess, quite abruptly at the point where a mother gives birth. 00:08:22.745 --> 00:08:26.665 They suddenly begin to express these maternal behaviors. And once the change 00:08:26.665 --> 00:08:28.805 has happened, it stays with you. 00:08:28.805 --> 00:08:31.865 Yes i guess for the rest of your life if you're a mother yes 00:08:31.865 --> 00:08:34.945 yeah and and for you that was a if you 00:08:34.945 --> 00:08:38.645 like a those were a cluster of markers which suggested epigenetics 00:08:38.645 --> 00:08:41.585 rather than some other mechanism yes and i should add to 00:08:41.585 --> 00:08:47.785 that um another clue really um was the fact that um hormones are involved in 00:08:47.785 --> 00:08:51.785 facilitating this mother-infant bond and facilitating the consolidation of maternal 00:08:51.785 --> 00:08:58.865 learning and um it's been established for quite some time that these steroid signaling pathways. 00:08:59.385 --> 00:09:02.125 Modify chromatin. 00:09:02.305 --> 00:09:06.585 And that's one of the ways that they lead to these sort of long-lasting effects. 00:09:07.045 --> 00:09:13.105 And so it seemed as another clue that particularly since I'm interested in this 00:09:13.105 --> 00:09:16.625 idea of hormones and experience somehow being interchangeable, 00:09:16.745 --> 00:09:21.845 and I've been really interested in whether or not there's a common molecular 00:09:21.845 --> 00:09:24.045 mechanism through which hormones or 00:09:24.185 --> 00:09:26.745 experience might be impacting behavior, 00:09:27.025 --> 00:09:31.465 it seemed as though maybe this would be a good candidate mechanism. 00:09:31.665 --> 00:09:40.465 And in support of this idea that it might be involving CREB and CREB-binding protein, 00:09:40.825 --> 00:09:45.745 there's also evidence that CREB is increased in the medial preoptic area, 00:09:45.865 --> 00:09:48.085 the central site for maternal behavior, 00:09:48.345 --> 00:09:51.485 and that that increase in CREB, you see this in virgin 00:09:51.485 --> 00:09:54.185 mice that are interacting with infants and you also see it 00:09:54.185 --> 00:09:57.285 in postpartum animals that are interacting with infants can 00:09:57.285 --> 00:10:01.645 you just unpack what you mean by kreb oh yes sorry 00:10:01.645 --> 00:10:05.365 so um so kreb is activated um 00:10:05.365 --> 00:10:12.565 through kreb for stands for cyclic amp response element um binding protein and 00:10:12.565 --> 00:10:17.165 uh kreb is a transcription factor that's activated um by neural activity and 00:10:17.165 --> 00:10:23.485 so um intracellular signaling cascades as a result of neurotransmitter binding can activate CREB. 00:10:23.505 --> 00:10:30.365 And when CREB is phosphorylated, it can turn on genes. And... 00:10:31.548 --> 00:10:35.888 This CREB-mediated gene transcription we know plays an important role in the 00:10:35.888 --> 00:10:39.148 consolidation of memories. 00:10:39.368 --> 00:10:45.368 You mutate CREB, you get disruptions in ability to learn and consolidate. 00:10:46.268 --> 00:10:51.488 But now, if we talk about maternal behaviors and also pregnancy, 00:10:51.908 --> 00:10:55.848 what is the overall hormonal profile that goes along with that? 00:10:55.968 --> 00:10:59.188 Because it's not like a single hormone that will impact that, 00:10:59.188 --> 00:11:01.488 right? No, it's definitely not a single hormone. 00:11:02.048 --> 00:11:06.948 However, that being said, the rise in estradiol, I think, plays a really important role. 00:11:07.068 --> 00:11:11.028 And there are other hormones that can act, I think, downstream of that. 00:11:11.148 --> 00:11:16.848 So for example, one of the things that this rise in estradiol does is that it 00:11:16.848 --> 00:11:23.928 can turn on oxytocin receptor gene expression. And so it sort of plays this 00:11:23.928 --> 00:11:25.388 role in priming the circuit. 00:11:26.008 --> 00:11:31.588 And so then when we get these surges in oxytocin, the receptors are there and present. 00:11:31.828 --> 00:11:36.008 So I sort of always think about things from estradiol's perspective since it's 00:11:36.008 --> 00:11:40.168 sort of the first wave and needed for some of these other hormone effects. 00:11:41.628 --> 00:11:45.708 But estradiol could also be a switch sitting at the beginning of a long cascade 00:11:45.708 --> 00:11:48.228 of responses to that switch. 00:11:48.908 --> 00:11:52.288 Yes, yes. Yeah. As you describe it also now. 00:11:52.648 --> 00:11:58.008 So then if you don't want to look at, let's say, the intrinsic components contributing 00:11:58.008 --> 00:12:03.208 to changes in behavior and the experiential components that are in the environment, 00:12:03.328 --> 00:12:06.328 and that would be key in an epigenetic perspective, 00:12:06.768 --> 00:12:09.728 how do you see this trade off against each other? 00:12:10.248 --> 00:12:13.988 Is it really like very strictly regimented? Like, okay, in this phase, 00:12:14.028 --> 00:12:15.048 we're under hormonal control. 00:12:16.528 --> 00:12:20.388 Now birth has taken place and now we're going to be under environmental control. 00:12:20.728 --> 00:12:22.628 Or are they more interleaved? 00:12:25.534 --> 00:12:29.894 I think they're more interweaved, although I'm not entirely sure what you mean 00:12:29.894 --> 00:12:31.054 by environmental control. 00:12:31.194 --> 00:12:35.314 You mean the experience? Experience, yes. The environment, right? Right. 00:12:35.434 --> 00:12:43.014 So I think that when it comes, I mean, I think that the hormones are allowing 00:12:43.014 --> 00:12:45.074 for the experiences to have a greater impact. 00:12:45.674 --> 00:12:48.674 And I don't think that the hormone, I think the hormones probably play a role 00:12:48.674 --> 00:12:51.574 in increasing attractiveness of infant stimuli. 00:12:51.574 --> 00:12:56.674 And in the RAP model, which is really where we know the most about the role 00:12:56.674 --> 00:13:01.074 of hormones, I think they're probably playing a role in reducing fear and avoidance 00:13:01.074 --> 00:13:03.094 tendencies towards the infants. 00:13:03.334 --> 00:13:08.594 But it's the experience of interacting with the infants in the context of those 00:13:08.594 --> 00:13:15.554 hormonal changes that really increases maternal care and leads to these long-term changes. 00:13:15.554 --> 00:13:18.934 And so if you just had those hormones, for example, if you were to, 00:13:19.154 --> 00:13:24.714 and this work was done by Alison Fleming, if you were to remove the pups just 00:13:24.714 --> 00:13:27.194 as the female was giving birth, and so when she did these experiments, 00:13:27.314 --> 00:13:31.734 she actually sort of had females giving birth in this cage where the pups could fall through. 00:13:31.734 --> 00:13:37.954 So she wasn't able to interact with the pups at all, but she did deliver them and give birth to them. 00:13:38.434 --> 00:13:42.794 You remove those pups immediately, you don't give her an opportunity to interact. 00:13:43.034 --> 00:13:48.234 She doesn't show any changes in her maternal responsiveness towards infants 00:13:48.234 --> 00:13:49.814 once those hormones have waned. 00:13:49.974 --> 00:13:54.114 So clearly those hormones can play a facilitary role, but I think their role 00:13:54.114 --> 00:13:58.954 is fairly useless unless infant stimuli are present for her to interact with 00:13:58.954 --> 00:14:00.754 under those hormonal changes. 00:14:00.754 --> 00:14:07.314 So these rats that delivered the pups and never handled themselves would not 00:14:07.314 --> 00:14:13.454 show any kind of, let's say, enhanced maternal response in future interaction 00:14:13.454 --> 00:14:15.274 with any other pups? Yes, that's correct. 00:14:15.434 --> 00:14:18.534 This is what you're saying. They behave as though they're the virgins. 00:14:18.694 --> 00:14:22.194 Mm-hmm. Okay. Yes, yes. So then what's... 00:14:23.428 --> 00:14:29.908 What's the key data that you have obtained to make the case for this sort of 00:14:29.908 --> 00:14:32.448 epigenetic interpretation of maternal behavior? 00:14:33.528 --> 00:14:39.508 Right now, I think my key work is really with using sodium butyrate, 00:14:39.588 --> 00:14:41.308 a histone deacetylase inhibitor. 00:14:41.308 --> 00:14:47.968 And so this is a drug which inhibits the deacetylation of histone proteins, 00:14:48.268 --> 00:14:54.288 allowing for increases in histone acetylation under certain events. 00:14:55.888 --> 00:14:58.408 For example, the experience of interacting with infants. 00:14:58.408 --> 00:15:06.348 And so when females are interacting with infants in the context of this particular 00:15:06.348 --> 00:15:09.108 drug, we see a facilitation of this learning effect, 00:15:09.388 --> 00:15:14.668 suggesting that there may be a histone acetylation component that naturally 00:15:14.668 --> 00:15:18.268 occurs when females are interacting with infants, 00:15:18.568 --> 00:15:20.528 leading to these long-term changes. 00:15:20.528 --> 00:15:26.588 So I think, because we're not molecular scientists, this is difficult for us. 00:15:26.648 --> 00:15:31.648 But the exciting thing I thought from your talk is that you think you've identified 00:15:31.648 --> 00:15:39.648 a cellular mechanism where experience is impacting directly or indirectly on 00:15:39.648 --> 00:15:45.288 the DNA and turning on and off the genes that generate maternal behavior. 00:15:45.288 --> 00:15:51.348 And so maybe we should just explore that because there are key ideas in your 00:15:51.348 --> 00:15:53.568 talk, like the idea of epigenetic marks, 00:15:53.828 --> 00:16:00.708 which seem to be very general and quite powerful ways through which developmental 00:16:00.708 --> 00:16:07.488 mechanisms and experience can impact on the expression of genes and therefore 00:16:07.488 --> 00:16:12.948 could lead to hereditable influences. 00:16:13.368 --> 00:16:18.248 So it's a way in which the environment can select for different phenotypes. 00:16:18.528 --> 00:16:23.388 So can you explain this idea of epigenetic marks and how that relates to these 00:16:23.388 --> 00:16:26.088 processes you're describing in the cell? Sure, definitely. 00:16:26.368 --> 00:16:33.148 So when we talk about epigenetic marks, we're really talking about a variety 00:16:33.148 --> 00:16:38.108 of post-translational modifications that can occur to the histone proteins that 00:16:38.108 --> 00:16:39.588 DNA is super coiled around. 00:16:39.888 --> 00:16:44.108 And so these modifications occur on the tails of the histone proteins, 00:16:44.228 --> 00:16:45.508 which sort of protrude out. 00:16:47.356 --> 00:16:53.356 And the marks can be phosphorylation, acetylation. So the DNA inside the cell 00:16:53.356 --> 00:16:57.216 is wrapped up inside of lots of other proteins. 00:16:57.676 --> 00:17:00.556 Yes, right. So we say the DNA is not… You've got to start easy with us. 00:17:00.576 --> 00:17:03.196 I'm sorry. You've got to start easy with me. Okay. I'm sorry. 00:17:03.756 --> 00:17:07.676 Yes, so the DNA, the phrase is the DNA is not naked in the nucleus, 00:17:07.956 --> 00:17:11.176 which we sometimes think, you know, that it is. 00:17:11.236 --> 00:17:15.756 I mean, I certainly didn't think much about histones before I got involved in epigenetic research. 00:17:15.756 --> 00:17:18.636 Research um and so but but the dna 00:17:18.636 --> 00:17:21.576 is not naked in the nucleus it is wrapped around these histone 00:17:21.576 --> 00:17:24.256 proteins and so the nucleosome which is 00:17:24.256 --> 00:17:27.556 the basic repeating unit um consists of 00:17:27.556 --> 00:17:34.436 a core octamer of histone protein so there's four proteins uh histone h uh h 00:17:34.436 --> 00:17:43.296 h1 is the linker we have h2 h uh h2a h2b um h3 and h4 and so and then we have 00:17:43.296 --> 00:17:46.376 two copies of each one of these and so they form this octamer. 00:17:46.836 --> 00:17:51.576 And they have, again, as I said, these long protruding tails, 00:17:51.716 --> 00:17:53.956 and these tails are where the modifications take place. 00:17:54.356 --> 00:18:00.856 And then around this octamer, you have about approximately 147 base pairs of DNA. 00:18:01.816 --> 00:18:07.456 And so the modifications can be acetylation, which is an acetyl group added 00:18:07.456 --> 00:18:09.196 to a particular residue. 00:18:09.696 --> 00:18:14.436 Frequently, it's a lysine residue of the histone protein tail. 00:18:14.676 --> 00:18:20.836 And this can occur on histone H3, histone H4, histone H2A, H2B. 00:18:21.876 --> 00:18:28.916 And in addition, you could also have methylation marks that occur on these tails, 00:18:29.116 --> 00:18:33.816 the histone protein tails, along with phosphorylation marks and ubiquitination. 00:18:34.036 --> 00:18:36.216 I mean, there's many different post-translational modifications. 00:18:36.656 --> 00:18:40.656 I think we know the most about acetylation, but I think we're we're starting 00:18:40.656 --> 00:18:43.316 to learn a bit about methylation. 00:18:43.696 --> 00:18:47.736 So just to be clear, so the DNA is wrapped up in this package with all these 00:18:47.736 --> 00:18:50.976 histones. In order for the DNA to become active. 00:18:52.002 --> 00:18:57.762 It has to be unwrapped in some way. And by attaching molecules onto these histone 00:18:57.762 --> 00:19:05.122 tails, then some external mechanism can decide which of the genes is allowed 00:19:05.122 --> 00:19:06.882 to express itself within that cell. 00:19:07.322 --> 00:19:10.602 Yes, you can sort of think about it. I like to think about it in the promoter 00:19:10.602 --> 00:19:11.982 region of a particular gene. 00:19:12.062 --> 00:19:15.562 And this promoter region is where the transcription factors are going to bind 00:19:15.562 --> 00:19:19.602 in order to turn on gene transcription. In this promoter region, 00:19:19.922 --> 00:19:24.102 you can have histone tails, right, sort of nearby. 00:19:24.342 --> 00:19:28.302 And these histone tails then can contain different types of marks. 00:19:28.462 --> 00:19:32.602 So I would argue the mark, at least the mark I'm the most familiar with, 00:19:32.702 --> 00:19:41.902 but I think a mark that is fairly well known is this acetyl group on histone H3 at lysine 9 or 14. 00:19:41.902 --> 00:19:48.222 And this mark is associated with actively transcribing genes across the whole genome. 00:19:48.302 --> 00:19:53.262 And so excellent genome-wide sequencing experiments have been done to look at this. 00:19:53.942 --> 00:20:00.682 And so this mark, and what acetyl marks typically do, is they can actually sort 00:20:00.682 --> 00:20:03.962 of loosen the association of the DNA and the histone. 00:20:03.962 --> 00:20:08.042 And so it sort of opens up physically the chromatin, allowing for transcription 00:20:08.042 --> 00:20:13.402 factors to more easily access gene promoters. 00:20:13.442 --> 00:20:16.042 And so it's easier for the gene to be turned on, essentially. 00:20:16.242 --> 00:20:22.822 So the idea is that experience with pups is having some effect on the cell, 00:20:22.942 --> 00:20:26.822 so that epigenetic marks are being generated, which are binding onto the histone, 00:20:26.882 --> 00:20:31.282 and then unlocking some genes which then generate maternal behavior. 00:20:31.282 --> 00:20:35.982 And this is exactly what I think, that with several experiences with the infant, 00:20:36.382 --> 00:20:41.562 that what we have is essentially an increase in histone acetylation. 00:20:41.822 --> 00:20:46.742 I haven't actually shown this yet. This is in the works. 00:20:47.422 --> 00:20:51.382 But what I have shown is an increase in the histone acetyltransferase, 00:20:51.542 --> 00:20:54.502 binding protein, binding protein, or CBP. 00:20:55.242 --> 00:21:00.482 And so, as I said, you know, CBP was my candidate because it sort of made sense 00:21:00.482 --> 00:21:03.522 with the whole Krebs story and learning and memory, et cetera. 00:21:03.862 --> 00:21:12.222 And so my hypothesis would be that there'd be an increase in the acetylation of H3K914. 00:21:12.382 --> 00:21:17.202 This is a mark that's associated with this Krebs-mediated gene transcription, 00:21:17.442 --> 00:21:24.002 CBP action, acetylation, and the consolidation of learning. So that would be my hypothesis. 00:21:24.982 --> 00:21:29.962 And there's also, you know, there's several other marks that I'm interested in exploring. 00:21:30.022 --> 00:21:32.862 And when you think about learning and memory, you always have to think about 00:21:32.862 --> 00:21:38.402 the other side of the coin too, which is, I think, inhibiting the expression 00:21:38.402 --> 00:21:44.042 of genes that would be reducing consolidation or reducing. 00:21:44.755 --> 00:21:46.295 Acting as a consolidation block. 00:21:46.795 --> 00:21:50.435 And so that's, I think, definitely a part of what I'd like to- Yeah. 00:21:50.535 --> 00:21:55.035 So there's this threshold process that it has to build up and there's another 00:21:55.035 --> 00:21:58.115 process going on, which is trying to deconstruct these. 00:21:58.615 --> 00:22:02.975 Absolutely. Now, in terms of the threshold, which I think this is sort of a 00:22:02.975 --> 00:22:05.875 perfect segue into, again, why I got interested in this. 00:22:06.655 --> 00:22:10.655 When you think about the fact that hormones are facilitating this process, 00:22:10.715 --> 00:22:15.515 and with hormones, we don't need so many days of experience, right? 00:22:15.555 --> 00:22:19.235 We can have very brief periods of experience and we can get these same effects 00:22:19.235 --> 00:22:21.055 in terms of maternal learning. 00:22:21.355 --> 00:22:27.235 And so what we know about estradiol is that estradiol can, when it binds to 00:22:27.235 --> 00:22:32.035 its receptor, translocates to the nucleus and is a transcription factor, 00:22:32.175 --> 00:22:34.295 which then turns on genes. 00:22:34.695 --> 00:22:37.695 And there's many genes that have estrogen response elements 00:22:37.695 --> 00:22:40.755 or respond to estradiol estrogen receptor 00:22:40.755 --> 00:22:43.835 complex um but part of that 00:22:43.835 --> 00:22:46.635 complex is actually cbp so 00:22:46.635 --> 00:22:49.515 cbp is recruited as part of that complex and 00:22:49.515 --> 00:22:57.135 so probably there are increases in histone acetylation um via cbp just with 00:22:57.135 --> 00:23:01.575 hormone exposure alone no it doesn't make sense because i thought you made a 00:23:01.575 --> 00:23:07.235 point earlier that the the histone acetylation would be dependent on the experience, 00:23:07.515 --> 00:23:10.175 because it would be the mediator to get the maternal behavior, 00:23:10.515 --> 00:23:16.215 and you already made the point earlier that just being pregnant and giving birth is not it, right? 00:23:16.375 --> 00:23:18.955 Yes, well, yes, that's absolutely true. 00:23:19.155 --> 00:23:25.535 And so, again, I think that the hormones are there, the hormones in this scenario 00:23:25.535 --> 00:23:28.235 where we have the surgeon estradiol. 00:23:30.001 --> 00:23:33.821 The pup inputs would also need to be present. And so I don't, 00:23:33.821 --> 00:23:35.661 I mean, you raise an excellent point. 00:23:35.761 --> 00:23:39.761 And I think the answer to this probably lies in understanding all of the genes 00:23:39.761 --> 00:23:43.441 that get turned on and what sort of the order of events is. 00:23:43.521 --> 00:23:48.641 So for example, estrogen receptor could be turning on a gene, 00:23:48.821 --> 00:23:52.601 which then affects, it could be turning on a transcription factor, 00:23:52.681 --> 00:23:54.341 which then affects another gene. 00:23:55.541 --> 00:23:59.001 Could be turning on, so they could be turning on different genes. 00:23:59.001 --> 00:24:05.101 And I don't know the specifics, and I think we actually know relatively little 00:24:05.101 --> 00:24:09.701 about the genes that are involved in these two separate processes. 00:24:10.141 --> 00:24:13.941 So I would like to get to behavior, but I don't know… There's a few more steps 00:24:13.941 --> 00:24:15.601 that I'd like to understand here. 00:24:15.701 --> 00:24:22.721 So the estradiol is sort of priming or facilitating an impact that the behavioral 00:24:22.721 --> 00:24:24.181 experience is going to have on the cell. 00:24:24.661 --> 00:24:34.821 No, we cannot say that because the virgin mice exposed to pups will also show maternal behavior. 00:24:34.961 --> 00:24:36.921 So you don't need the estradiol to do anything. 00:24:37.141 --> 00:24:41.381 Well, you don't need the estradiol, but it still plays a facilitary role. But it's not required. 00:24:41.781 --> 00:24:44.421 But it's not required. Yeah. I think that's what we're saying is that if it's 00:24:44.421 --> 00:24:45.461 there, it makes it easier. 00:24:46.201 --> 00:24:49.601 Well, does it reduce the threshold of exposure? Yes. I don't think you showed that. 00:24:49.781 --> 00:24:54.121 No, I did not show that. No, but that's… I thought in all cases it was four 00:24:54.121 --> 00:24:56.201 exposures that we were talking about. 00:24:56.501 --> 00:25:00.841 So, in my, that's, so, that's what I've shown. But it's. 00:25:01.635 --> 00:25:05.375 Very well established in the literature that estradiol produces 00:25:05.375 --> 00:25:08.435 very rapid effects compared to experience takes a 00:25:08.435 --> 00:25:13.655 bit longer um what i showed with four experiences with postpartum females which 00:25:13.655 --> 00:25:17.235 is correct is i wanted to show that if we match the amount of experience that 00:25:17.235 --> 00:25:21.775 we would get the same level of responsiveness between a postpartum animal um 00:25:21.775 --> 00:25:25.555 and uh and a virgin or ovariectomized experience to females. 00:25:26.275 --> 00:25:27.575 Let's say it's a facilitator. 00:25:28.435 --> 00:25:29.535 Let's finish on the mechanism. 00:25:30.655 --> 00:25:35.795 And so the cells that this is operating on, you found were a specific group 00:25:35.795 --> 00:25:37.455 of cells in the hypothalamus. Is that right? 00:25:37.735 --> 00:25:42.735 Yes. So my effects are, in terms of turning on genes, have been found in the 00:25:42.735 --> 00:25:44.555 medial preoptic area of the hypothalamus, yes. 00:25:44.815 --> 00:25:48.615 And why did you look in that bit of the brain, or did you look more widely? 00:25:48.935 --> 00:25:52.115 I did look more widely, but I chose 00:25:52.115 --> 00:25:54.935 the medial preoptic area because it's considered the central neural site 00:25:54.935 --> 00:25:57.915 for maternal care um and so for example 00:25:57.915 --> 00:26:01.695 if you lesion the medial pre-optic area you disrupt maternal behavior um 00:26:01.695 --> 00:26:04.855 and if uh if you stimulate it uh 00:26:04.855 --> 00:26:07.715 with hormones um uh you 00:26:07.715 --> 00:26:10.575 can facilitate the onset of maternal behavior um if 00:26:10.575 --> 00:26:13.875 you stimulate it with the dopamine agonist 00:26:13.875 --> 00:26:16.635 you can facilitate the onset of maternal behavior and that 00:26:16.635 --> 00:26:19.795 work has been been done mostly in rat but so are 00:26:19.795 --> 00:26:23.655 you saying that your hypothesis 00:26:23.655 --> 00:26:29.935 is that some combination of hormone and experience is switching on a population 00:26:29.935 --> 00:26:35.855 of hypothalamic cells so that some some genes which are important for maternal 00:26:35.855 --> 00:26:40.535 behavior are now on and previously they weren't yes that's correct that is that 00:26:40.535 --> 00:26:43.515 is correct but also can you say to follow up on that. 00:26:44.162 --> 00:26:51.262 That it exclusively happens there, so that either estradiol release or exposure 00:26:51.262 --> 00:26:57.742 to PAPs does not lead to histone acetylase in any other neuron in the brain. 00:26:58.282 --> 00:27:02.982 No, and I don't think that that's the case. I think that absolutely there are 00:27:02.982 --> 00:27:07.582 other regions within the circuit that we already know are important for maternal 00:27:07.582 --> 00:27:10.822 memory in terms of what's… But they would show the same effect. 00:27:11.022 --> 00:27:15.122 They would also show histone acetylase in response to these stimuli. 00:27:16.342 --> 00:27:21.142 I think that they would. I just haven't found them yet. Yeah. 00:27:21.482 --> 00:27:25.922 So, you know, I've always been very interested in the role of the mesolimbic 00:27:25.922 --> 00:27:28.582 dopamine system in maternal behavior and maternal motivation. 00:27:28.622 --> 00:27:34.482 And so one of the areas that I looked in addition to the pre-optic area was the nucleus accumbens. 00:27:34.482 --> 00:27:37.622 Um the genes that i chose as candidates did 00:27:37.622 --> 00:27:40.722 not change in the nucleus accumbens um at 00:27:40.722 --> 00:27:43.462 any of the time points so the um so i 00:27:43.462 --> 00:27:46.382 most of the work that i showed you was with the 24 hours 00:27:46.382 --> 00:27:49.322 after their experience looking at gene expression there 00:27:49.322 --> 00:27:56.962 but the um the uh uh time course that i did with um uh 30 minutes and five hours 00:27:56.962 --> 00:28:02.502 and 24 hours which um which was a which was a full experiment it just It just 00:28:02.502 --> 00:28:06.862 wasn't published because there were no other effects at any other time point, right? 00:28:07.342 --> 00:28:11.662 And there were no effects that I could find in the nucleus accumbens. 00:28:12.502 --> 00:28:17.282 So I certainly think that something is happening in the nucleus accumbens. 00:28:17.282 --> 00:28:21.242 I just could not believe that there would be no change there. 00:28:21.342 --> 00:28:23.262 I just haven't located the change yet. 00:28:23.871 --> 00:28:30.531 So to get to the behavior, so we have some activity in the hypothalamus that 00:28:30.531 --> 00:28:36.351 wasn't there before, which is triggering maternal responses to pups. 00:28:36.411 --> 00:28:43.011 And the indicator of that which you've been using is whether a female rat will 00:28:43.011 --> 00:28:47.791 retrieve a pup that's isolated away from the nest and would die without help. 00:28:47.971 --> 00:28:52.311 Exactly. And there's various measures of that, one being the time it takes for 00:28:52.311 --> 00:28:54.751 the female rat to retrieve. 00:28:54.991 --> 00:29:00.011 I think you had three pups. Yes. But you were also talking about other measures 00:29:00.011 --> 00:29:03.231 of maternal behavior, for instance, licking and grooming. 00:29:03.691 --> 00:29:08.231 And I think you said that these don't all appear at once. Is that right? 00:29:08.331 --> 00:29:14.491 If it's a virgin rat or if it's just happening that these are maybe triggered 00:29:14.491 --> 00:29:19.891 at different times? What you usually see is sort of this stereotyped onset, 00:29:20.151 --> 00:29:22.791 which flows sequentially. 00:29:22.971 --> 00:29:28.571 So when you put the pups into a virgin female's home cage, which is how we start 00:29:28.571 --> 00:29:33.471 all of our experiments, and you sort of scatter them out, what the female typically 00:29:33.471 --> 00:29:35.531 will do is she'll sniff them immediately. 00:29:35.531 --> 00:29:38.411 Immediately um and she'll sort of run from 00:29:38.411 --> 00:29:41.491 each you know pup to pup sort of sniffing she might 00:29:41.491 --> 00:29:44.871 sort of handle the pup and lick it a little bit um but 00:29:44.871 --> 00:29:47.731 usually um she'll engage in sort 00:29:47.731 --> 00:29:51.571 of just this sort of sniffing and walking around and investigating the infants 00:29:51.571 --> 00:29:57.851 for um several minutes if this is the first day for example and then what you 00:29:57.851 --> 00:30:02.331 typically see is um one of two things sometimes you'll see a female come out 00:30:02.331 --> 00:30:05.211 and retrieve start to retrieve the pups immediately 00:30:05.451 --> 00:30:08.411 sometimes what you'll see is her actually 00:30:08.411 --> 00:30:11.251 attempt to build a nest first and then come 00:30:11.251 --> 00:30:14.331 out and retrieve the pups to the nest now i've 00:30:14.331 --> 00:30:19.731 worked with rats and with mice and i can tell you that when when you see this 00:30:19.731 --> 00:30:25.711 onset of behavior in rat it's very stereotypical and it is very much like a 00:30:25.711 --> 00:30:32.591 switch it's a it's a very sort of all of a sudden on behavior and they're very very organized. 00:30:33.111 --> 00:30:37.471 And they sort of, when they decide that they're going to retrieve the pups, 00:30:37.531 --> 00:30:40.451 they come out, they retrieve the pups, they group them back at the nest, 00:30:40.551 --> 00:30:43.871 they lick and groom them, and then they sort of rest, 00:30:43.991 --> 00:30:47.751 you know, they become more quiescent in a crouched posture as though they were 00:30:47.751 --> 00:30:49.291 nursing. Obviously, they're not lactating. 00:30:50.091 --> 00:30:55.551 The process in mouse is a little bit less organized. 00:30:55.811 --> 00:31:00.311 It's one of the reasons why I decided to look at experience in mouse. 00:31:01.211 --> 00:31:05.131 So again, you might see retrieval right away. You might see nest building first. 00:31:05.511 --> 00:31:08.791 And often when they retrieve the pups, they don't actually put them into the 00:31:08.791 --> 00:31:11.911 nest on the first time. They put them outside of the nest. 00:31:12.031 --> 00:31:15.111 And then they sort of obsessively fling bedding around. 00:31:15.271 --> 00:31:18.991 And sometimes the pups fall out. It sort of takes them a little while to figure 00:31:18.991 --> 00:31:23.531 out exactly how to get the pups into the nest and how to get on top of the pups in the nest. 00:31:24.717 --> 00:31:29.757 Which is something you don't see in rat. And so once the female has sort of 00:31:29.757 --> 00:31:32.157 grouped the pups, then she'll start to lick the pups. 00:31:32.637 --> 00:31:37.357 And then again, she'll begin to quote unquote nurse. 00:31:37.437 --> 00:31:40.857 She'll adopt a crouching position over the pups. And then she typically stays 00:31:40.857 --> 00:31:43.117 with the pups for long periods of time. 00:31:43.997 --> 00:31:49.337 And I should note when females are on, when I've done these experiments with the HDAC inhibitor. 00:31:49.957 --> 00:31:53.577 We don't see differences um really 00:31:53.577 --> 00:31:56.397 in in these other behaviors in the 00:31:56.397 --> 00:31:59.437 home cage so the experience that an a virgin 00:31:59.437 --> 00:32:02.697 female getting regular water versus a virgin female 00:32:02.697 --> 00:32:05.537 getting the h-deck inhibitor the experiences they have with the pups 00:32:05.537 --> 00:32:10.297 appear to be similar so we don't see more licking and grooming for example um 00:32:10.297 --> 00:32:14.357 it's the impact of that experience that seems to be different based on their 00:32:14.357 --> 00:32:21.097 subsequent behavior on the maze so the h-deck inhibitor inhibits inhibits the 00:32:21.097 --> 00:32:23.977 histone as Histone deacetylase. 00:32:24.137 --> 00:32:28.137 And so it's sort of, it's allowing, I like to describe it as it's allowing for 00:32:28.137 --> 00:32:29.117 more histone acetylation. 00:32:29.197 --> 00:32:33.817 It's not directly acetylating histones. It's allowing for any histone acetyl 00:32:33.817 --> 00:32:38.797 transferases that are activated to become activated for longer, 00:32:38.897 --> 00:32:44.457 to acetylate histones without HDACs coming along and ripping the acetyl groups 00:32:44.457 --> 00:32:46.317 off. But then how do we interpret this effect? 00:32:46.477 --> 00:32:52.817 Because the histone STLase is correlated with memory consolidation, right? 00:32:52.897 --> 00:32:56.077 So if you now have a disinhibitor of that, you would expect, 00:32:56.317 --> 00:33:00.817 what would be the effect you expect on consolidation? It should amplify consolidation. 00:33:01.337 --> 00:33:06.597 Yes, yes. But actually, that's not what you see when you apply this HDAC. 00:33:06.597 --> 00:33:10.457 No, you do see an amplification of consolidation. 00:33:10.897 --> 00:33:16.077 So rather than requiring four experiences with pups, these animals only require two. 00:33:16.437 --> 00:33:19.937 Okay. Do you see also an invigoration of the behavior? Like the probability 00:33:19.937 --> 00:33:21.257 to build a nest is higher? 00:33:22.257 --> 00:33:27.777 So the experiences that they have, again, in the home cage are not different. 00:33:28.537 --> 00:33:34.497 So the behaviors that we see them engaging in while they're having these experiences 00:33:34.497 --> 00:33:36.857 are not different. It's just how they respond on the maze. 00:33:37.037 --> 00:33:42.177 They respond faster and they retrieve more pups. 00:33:43.517 --> 00:33:47.477 Okay. So now how do you explain the specificity of this effect? 00:33:47.477 --> 00:33:50.177 Book so to examine the 00:33:50.177 --> 00:33:54.557 specificity of the effect um because the behavioral 00:33:54.557 --> 00:33:58.457 effect that we're seeing is really that they're rescuing quote-unquote these 00:33:58.457 --> 00:34:02.497 pups from this sort of novel and fear-inducing environment um the first thing 00:34:02.497 --> 00:34:05.237 that i looked at was whether or not these animals had a reduction in anxiety 00:34:05.237 --> 00:34:11.017 and we don't see any changes in their behavior on an elevated plus maze with the hdac inhibitor. 00:34:11.117 --> 00:34:17.297 Uh, we don't see them responding, um, more to, um, objects that aren't pups, 00:34:17.337 --> 00:34:21.117 but are the same size and shape of pups. Um, and, 00:34:22.593 --> 00:34:26.413 Those are the two main sort of behavioral specificity experiments that we've done. 00:34:26.473 --> 00:34:31.833 But it might be possible that what you're looking at is also a nonspecific memory effect, right? 00:34:31.873 --> 00:34:37.293 I imagine you would have your animals perform a maze task or any task involving 00:34:37.293 --> 00:34:41.833 memory, that also there you would see amplification of performance because you 00:34:41.833 --> 00:34:43.873 just boost memory in a nonspecific way. 00:34:44.093 --> 00:34:51.293 I think that that's possible, but I don't think that it's necessarily likely, and I'll explain. 00:34:52.593 --> 00:34:56.213 And I'm certainly not the only person who's used sodium butyrate or an HDAC 00:34:56.213 --> 00:34:57.613 inhibitor to facilitate behavior. 00:34:57.913 --> 00:35:03.413 What you typically will see in experiments when people do this is the only effects 00:35:03.413 --> 00:35:07.333 that you get with the HDAC inhibitor rely on whatever the animal was learning 00:35:07.333 --> 00:35:11.093 when it was being treated with the HDAC inhibitor. 00:35:11.093 --> 00:35:14.373 And I think this speaks to the mechanism of how the inhibitor works. 00:35:14.553 --> 00:35:19.813 It's allowing for increases in histone acetylation. It's not globally increasing histone acetylation. 00:35:20.013 --> 00:35:26.153 And so what that would mean then is that if other areas of the brain weren't 00:35:26.153 --> 00:35:30.993 responsive to pup inputs or if other circuits that would consolidate memories 00:35:30.993 --> 00:35:33.053 were not being activated, 00:35:33.253 --> 00:35:36.073 which I would argue they wouldn't be because these animals are just interacting 00:35:36.073 --> 00:35:40.093 with pups, then you wouldn't get activation of HATs. 00:35:41.093 --> 00:35:45.473 In those regions. Sure. And so therefore it would basically not matter. 00:35:45.613 --> 00:35:50.153 But then if we would take the same mice and do let's say a place preference task. 00:35:50.873 --> 00:35:54.873 Right. Yes. Under the same manipulation you would predict. I would predict yes. 00:35:54.873 --> 00:35:56.953 That they would learn this also more rapidly. 00:35:58.333 --> 00:36:02.233 I would predict. Yeah well I guess I would predict that. 00:36:02.293 --> 00:36:05.733 Because I would say that their motivation is amped up. Because that's one of 00:36:05.733 --> 00:36:08.033 the things that I think maternal learning does. 00:36:08.493 --> 00:36:10.493 So then the histone acetylase itself. 00:36:11.093 --> 00:36:16.273 It's not specific to the maternal behavior, but it is affecting the memory component 00:36:16.273 --> 00:36:20.513 that feeds into, in this case, maternal behavior, because that's what you're 00:36:20.513 --> 00:36:21.513 triggering in the animal. 00:36:22.473 --> 00:36:25.913 Sorry, let me clarify my last statement. When you said conditioned place preference, 00:36:26.113 --> 00:36:28.493 I was thinking conditioned place preference for pups. 00:36:28.653 --> 00:36:33.373 No, no, no. I would mean just like with using rewards or stimuli. 00:36:34.553 --> 00:36:37.633 I don't know. I don't think that it would affect that. I do think it would affect 00:36:37.633 --> 00:36:40.293 a conditioned place preference for pups, which people do all the time. 00:36:40.293 --> 00:36:44.433 So I think it would affect another sort of memory pup-related task. 00:36:44.613 --> 00:36:50.093 I don't think that it would necessarily extend to a general learning and memory. 00:36:50.193 --> 00:36:55.173 Although I think the issue with that that would make it difficult to ask that 00:36:55.173 --> 00:36:57.013 question is that we already know 00:36:57.013 --> 00:37:00.813 that experience with infants facilitates learning and memory generally. 00:37:01.693 --> 00:37:06.373 So we wouldn't know if it was necessary. I mean, we'd have to do the full experiment 00:37:06.373 --> 00:37:10.173 to ensure that it wasn't just… But you have not done these controls to rule this out. No. 00:37:12.394 --> 00:37:13.834 Might be a nice thing to try. Yeah, 00:37:13.834 --> 00:37:17.494 well, I agree. There's a long list of experiments that I'd like to run. 00:37:18.574 --> 00:37:23.874 So the hypothalamus is a conserved structure in vertebrates, 00:37:23.934 --> 00:37:28.054 but maternal behavior is a marker of mammals. 00:37:28.254 --> 00:37:31.954 And I don't think other vertebrates care for their young. 00:37:32.154 --> 00:37:34.874 Certainly they don't give them the same amount of attention that mammals do. 00:37:35.154 --> 00:37:40.274 So it would be interesting, I guess, in the future to find out whether this 00:37:40.274 --> 00:37:44.654 mechanism that you've described, if that's how it operates, 00:37:45.134 --> 00:37:48.954 whether that is something that originates with early mammals, 00:37:49.134 --> 00:37:55.234 and whether it's operating throughout different mammal groups as well as in rodents. 00:37:55.434 --> 00:38:00.854 I mean, do you have any ideas in that direction, or do you have goals as to 00:38:00.854 --> 00:38:02.834 how you're going to answer those kinds of questions? 00:38:03.214 --> 00:38:06.134 I think that's a really interesting point, and I 00:38:06.134 --> 00:38:08.854 don't have any experiments planned to address that but i think 00:38:08.854 --> 00:38:11.654 it would be very interesting i mean the medial pre-optic area is also 00:38:11.654 --> 00:38:14.754 involved in other sorts of things in addition to maternal 00:38:14.754 --> 00:38:20.094 care right um but uh but certainly that's you know i mean it's involved in sexual 00:38:20.094 --> 00:38:24.534 behavior as well but right um but it definitely does play a very central role 00:38:24.534 --> 00:38:27.754 in maternal care so i think it would be interesting do you think this this mechanism 00:38:27.754 --> 00:38:32.254 you're describing uh is is going to be happening for instance in primates. 00:38:33.074 --> 00:38:37.454 Yes, I definitely think that it could be happening in primates. 00:38:38.174 --> 00:38:41.194 But then to look again at the hypothalamus, right? 00:38:41.814 --> 00:38:47.494 Hypothalamus to actually trigger behavior has to actually drive other structures, 00:38:47.674 --> 00:38:49.974 right? It has to talk with brainstem structures. 00:38:50.274 --> 00:38:52.394 We talked about central gray. 00:38:54.138 --> 00:38:58.558 And associated areas where you really know behaviors are encoded, right? 00:38:58.578 --> 00:39:01.538 So the behavior itself doesn't come from your hypothalamus. Hypothalamus is 00:39:01.538 --> 00:39:06.418 like setting if you want to switch or a signal like, okay, now we're going to go maternal, right? 00:39:06.618 --> 00:39:11.998 Yes. So what's that circuit in which it's embedded that we should consider in this case? 00:39:12.398 --> 00:39:16.398 So that's an excellent question. The circuit and really the way that I think 00:39:16.398 --> 00:39:19.878 about it is I am not that interested in the stereotyped behaviors. 00:39:19.878 --> 00:39:24.098 I'm interested in the medial preoptic area and its interactions with the mesolimbic 00:39:24.098 --> 00:39:28.678 dopamine system to get at sort of this general motivation for infants so that 00:39:28.678 --> 00:39:31.638 if I put them in any sort of environment, they would be responsive. 00:39:31.638 --> 00:39:37.338 And so the medial preoptic area gets inputs from every sensory domain, 00:39:37.578 --> 00:39:42.078 and it projects to many regions. 00:39:42.338 --> 00:39:46.118 But the aspect of the circuit that I've always been most interested in is the 00:39:46.118 --> 00:39:49.998 aspect that seems to regulate these changes in maternal responsiveness, 00:39:50.118 --> 00:39:52.498 this maternal motivation or this increase in care. 00:39:52.498 --> 00:39:59.638 And that aspect of the circuit is mediated by these pre-optic connections to 00:39:59.638 --> 00:40:04.778 the ventral tegmental area, which cause the release of dopamine into the nucleus accumbens. 00:40:05.278 --> 00:40:10.798 And the nucleus accumbens receives inputs from the basolateral amygdala, 00:40:10.918 --> 00:40:15.538 the prefrontal cortex, and those regions also project to the ventral pallidum. 00:40:15.578 --> 00:40:19.078 And so there's important interactions between the nucleus accumbens and the ventral pallidum. 00:40:21.360 --> 00:40:26.220 I definitely think that that part of the circuit is another place where memories can be consolidated. 00:40:26.580 --> 00:40:29.620 What I think is probably happening in the medial preoptic area, 00:40:29.800 --> 00:40:34.520 it's probably the connections between, and I have no evidence for this, 00:40:34.580 --> 00:40:35.800 this is just my hypothesis, 00:40:36.120 --> 00:40:39.380 the connections between the medial preoptic area and the ventral tegmental area 00:40:39.380 --> 00:40:44.820 are somehow strengthened so that we're getting a more consistent and robust 00:40:44.820 --> 00:40:50.780 release of dopamine in the nucleus When experienced females interact with pups. 00:40:50.860 --> 00:40:55.740 And this idea comes from some work also done by Alison Fleming, 00:40:55.780 --> 00:41:01.800 where she shows in RAT that as females, pregnant postpartum females, 00:41:01.880 --> 00:41:03.140 as they have experience with infants, 00:41:03.420 --> 00:41:09.540 that they have more dopamine release via microdialysis into the nucleus accumbens 00:41:09.540 --> 00:41:12.980 than do females that have just interacted with pups. 00:41:12.980 --> 00:41:16.920 So is this, could we then interpret this circuit? 00:41:16.960 --> 00:41:22.780 If you talk about VTA and a nucleus accumbens, we're talking about the processing 00:41:22.780 --> 00:41:29.300 of value and effect and valence and so on, not necessarily the information that we want to reinforce. 00:41:29.620 --> 00:41:32.840 But there's a mechanism of reinforcing a behavior. 00:41:32.840 --> 00:41:37.000 Behavior so would it then look like the hypothalamus 00:41:37.000 --> 00:41:40.740 is just signaling to the rest of the brain okay we're 00:41:40.740 --> 00:41:43.640 dealing with pups and and then these effect 00:41:43.640 --> 00:41:46.420 related areas vta nucleus accumbens say yeah and 00:41:46.420 --> 00:41:52.100 it is great and using that signal you reinforce behavioral patterns that allow 00:41:52.100 --> 00:41:55.320 it to be more effective in dealing with pups would that be the cascade yes i 00:41:55.320 --> 00:41:59.960 agree and there's some projections that are back go feed back to the medial 00:41:59.960 --> 00:42:03.820 pre-optic areas so that would that make But then the medial preoptic area could 00:42:03.820 --> 00:42:05.560 be, let's say, your specialized detector, 00:42:05.840 --> 00:42:12.000 if you want, for maternally relevant states of the world. Like, 00:42:12.020 --> 00:42:12.920 oh, there are pups around. 00:42:13.200 --> 00:42:15.800 I should do something. Is this roughly how we should think about it? 00:42:15.800 --> 00:42:18.080 Yeah, I think that maybe. Yes, yes. Okay. But then…. 00:42:21.435 --> 00:42:27.015 So, you would see then this preoptic area in hypothalamus as the signaler who 00:42:27.015 --> 00:42:29.815 triggers this behavior, right? 00:42:29.935 --> 00:42:33.855 Yes. But then that also means there's already on the one hand a predefined circuit 00:42:33.855 --> 00:42:35.875 that says, okay, there's a pup there. 00:42:36.175 --> 00:42:41.035 There are stereotype behaviors that you can like collecting pups and dragging them around. 00:42:41.035 --> 00:42:46.175 And then there are areas that, let's say, are more frontal in the brain that says, okay, 00:42:46.355 --> 00:42:49.275 and this is what the world looks like, and this is the specific properties of 00:42:49.275 --> 00:42:53.215 the pup I should learn about, and so on, that then I'm reinforcing by talking, 00:42:53.295 --> 00:42:56.135 by driving these more effect-related areas. 00:42:56.315 --> 00:42:59.015 Yes. That would be the sort of story. Yes. 00:42:59.795 --> 00:43:05.275 If we talk about epigenetic and genetic, then the more epigenetic part would 00:43:05.275 --> 00:43:09.635 then be sitting more in these more frontal areas, or not? 00:43:10.355 --> 00:43:14.595 So where does the genetic begin and end, and where does it become epigenetic? 00:43:15.395 --> 00:43:20.935 I think that really when I think about genetics, I'm thinking about these patterns 00:43:20.935 --> 00:43:26.395 of genes that might need to be turned on in order to maintain this maternal state. 00:43:27.155 --> 00:43:32.855 And so some of these genes, as I mentioned in my talk, estrogen receptor beta, 00:43:33.035 --> 00:43:36.555 I see, for example, upregulated for long periods of time. 00:43:36.555 --> 00:43:39.455 Um and you know i should mention 00:43:39.455 --> 00:43:42.335 that francis champagne's work which shows that early life 00:43:42.335 --> 00:43:46.035 experience can modify initial maternal 00:43:46.035 --> 00:43:50.875 responses to infants and postpartum females as regulated by an upregulation 00:43:50.875 --> 00:43:56.555 of estrogen receptor alpha and so um so i think this sort of long-lasting change 00:43:56.555 --> 00:44:01.435 in estrogen receptor beta um would be the epigenetic part but you can't have 00:44:01.435 --> 00:44:03.955 that without without the actual gene of estrogen receptor beta. 00:44:04.575 --> 00:44:07.855 In terms of the other areas of the circuit, as I said, I haven't found anything 00:44:07.855 --> 00:44:11.235 yet, but I certainly think that there are likely changes there. 00:44:12.827 --> 00:44:18.187 It's convenient to focus on the medial preoptic area because although it's playing 00:44:18.187 --> 00:44:23.747 this sort of central role and interacts with all these different regions, 00:44:23.907 --> 00:44:26.307 it's also always necessary for maternal behavior. 00:44:26.507 --> 00:44:30.987 So maternal behavior does not become independent of the medial preoptic area 00:44:30.987 --> 00:44:33.747 that we can find in our models. 00:44:34.167 --> 00:44:38.047 And so it seems like a really likely place that would need to be permanently 00:44:38.047 --> 00:44:41.307 changed and maintained in that maternal state for long periods of time. 00:44:41.307 --> 00:44:45.247 So I think when we think of the hypothalamus, we think of a motivational center. 00:44:45.327 --> 00:44:50.107 And in a sense, what's happening here is that you're turning on a part of the 00:44:50.107 --> 00:44:55.067 hypothalamus, which then motivates animals to express maternal behavior. 00:44:55.167 --> 00:45:01.367 The behavior themselves are triggered by other cues like there's a pup there, I'll look after it. 00:45:01.467 --> 00:45:05.807 But what the hypothalamus is doing is ensuring that motivational circuits and 00:45:05.807 --> 00:45:10.647 the reward circuits operate to reinforce that behavior. So it's a very nice 00:45:10.647 --> 00:45:15.267 idea and a nice explanation of what people might call the mothering instinct. 00:45:16.587 --> 00:45:19.227 But also what I like about this is 00:45:19.227 --> 00:45:26.487 it's a nice example of a non-genetic mechanism, which you can see how... 00:45:27.482 --> 00:45:33.602 During evolution, this happens and then it happens repeatedly and reliably sufficient 00:45:33.602 --> 00:45:38.242 that it can be passed on to later generations without having to have any genetic 00:45:38.242 --> 00:45:40.382 change. Yeah, and I think that's an excellent point. 00:45:40.542 --> 00:45:44.062 So, I mean, obviously, you know, I think we have certainly moved past, 00:45:44.182 --> 00:45:48.422 as a scientific culture, the idea of, you know, any one gene being critical 00:45:48.422 --> 00:45:50.782 for something as complex as mothering. 00:45:50.822 --> 00:45:56.262 But certainly, if there was sort of an evolution and changing in terms of responsiveness 00:45:56.262 --> 00:46:00.142 towards infants, it makes sense that you would have this epigenetic change where 00:46:00.142 --> 00:46:01.842 you're sort of using the genes that you already have. 00:46:02.182 --> 00:46:06.742 But this change then is altering the way they're regulated in order to ensure 00:46:06.742 --> 00:46:10.602 care. But just for clarity, also to clarify what Tony is saying, 00:46:10.702 --> 00:46:12.502 because otherwise I might not agree with him. 00:46:13.202 --> 00:46:19.382 Isn't it the case that we could argue that basically genetically a certain potential 00:46:19.382 --> 00:46:24.322 set of behaviors and potential behaviors are defined? 00:46:24.662 --> 00:46:33.442 But now you need very specific environmental triggers to actually unveil that set of behaviors or not. 00:46:33.702 --> 00:46:37.062 Yes. This would be the epigenetic switch. switch yeah we 00:46:37.062 --> 00:46:39.802 agree i agree don't you agree with that or get something else in 00:46:39.802 --> 00:46:42.662 mind but that's not non-genetic it's just 00:46:42.662 --> 00:46:45.642 you need an environmental trigger to now also start 00:46:45.642 --> 00:46:50.722 to run a specific also genetically predefined program you have to have an environment 00:46:50.722 --> 00:46:55.222 which is predictable in such a way that this happens despite there not being 00:46:55.222 --> 00:46:59.642 any genetic modification but it happens and therefore you can rely on it happening 00:46:59.642 --> 00:47:04.702 in future generations so that you can consider it as a something that can be selected. 00:47:04.882 --> 00:47:09.162 Sure. No, I was just trying to be clear about what you meant with non-genetic, 00:47:09.162 --> 00:47:14.562 but that's the trigger, the triggering of genetically predefined behavioral programs as well. 00:47:15.483 --> 00:47:19.863 Well, yes. It's not like strictly non-genetic. I think that would be a bit too 00:47:19.863 --> 00:47:22.263 extreme. No, I think that's true. It's not strictly non-genetic. 00:47:22.403 --> 00:47:25.863 I think that any time that you talk about epigenetics, you have to talk about genetics. 00:47:26.003 --> 00:47:28.303 They go hand in hand. But what I got from what you were saying, 00:47:28.403 --> 00:47:32.063 which I don't know if this is the case, but I thought that you were indicating 00:47:32.063 --> 00:47:34.183 that there wasn't some new mutation that arose. 00:47:34.543 --> 00:47:37.203 Yes, that's what I'm trying to say. And that mutation then was… Right. 00:47:37.203 --> 00:47:41.063 And that's, I think, the best… I mean, this is why I like to sort of rely on 00:47:41.063 --> 00:47:45.403 these molecular or cellular definitions of epigenetics. it makes it a lot clearer. 00:47:45.583 --> 00:47:48.983 So when you talk about a gene mutation, that is strictly genetic. 00:47:49.603 --> 00:47:54.803 Whereas when we talk about epigenetic, we're talking about altered expression of particular genes. 00:47:55.083 --> 00:48:00.863 Right, but then the next question in some sense is, okay, how deep and primitive, 00:48:01.043 --> 00:48:07.523 if you want, is this genetic pre-specification, right, on which we then run 00:48:07.523 --> 00:48:08.643 these epigenetic switches? 00:48:09.163 --> 00:48:17.123 And there you showed that male mice, at least the lab mice after exposure can 00:48:17.123 --> 00:48:18.923 also display maternal behaviors. 00:48:19.283 --> 00:48:24.643 So this might seem confusing because you could argue also from an evolutionary 00:48:24.643 --> 00:48:29.763 perspective, we don't need to set up these genetically predefined behavioral 00:48:29.763 --> 00:48:31.863 programs to show maternal behavior, 00:48:32.203 --> 00:48:36.443 yet your mice show it. So how do you explain that? 00:48:38.263 --> 00:48:43.683 Well, I would argue that the circuit that's regulating maternal behavior is conserved. 00:48:44.103 --> 00:48:48.503 And I would argue that what we're seeing in these laboratory male mice is we're 00:48:48.503 --> 00:48:49.643 seeing really maternal behavior. 00:48:49.803 --> 00:48:53.963 So they're not like by parental species where we're seeing individual fathering 00:48:53.963 --> 00:48:55.803 behaviors that are different than the mothering behaviors. 00:48:55.903 --> 00:48:59.263 We're seeing the male mice display mothering behaviors. 00:49:00.063 --> 00:49:05.283 And so what I would argue is that everything that they need to do that is there. 00:49:05.383 --> 00:49:09.143 But what typically happens is that those processes are inhibited by, 00:49:10.223 --> 00:49:16.043 and this is clear in the rat, that there's really two aspects of the maternal neural circuit. 00:49:16.123 --> 00:49:20.303 There's an aspect which is in place to actually inhibit maternal care. 00:49:20.683 --> 00:49:23.983 And this circuit is what's active in virgin female rats. 00:49:24.403 --> 00:49:28.683 And what prevents them from retrieving pups upon initial exposure, 00:49:28.803 --> 00:49:30.583 what causes them to avoid pups. 00:49:31.223 --> 00:49:34.943 And this has to do with olfactory inputs, activating the anterior hypothalamus. 00:49:34.943 --> 00:49:39.863 And having an inhibitory input on the medial preoptic area. 00:49:41.523 --> 00:49:45.143 To my knowledge, no one has looked at that aspect of the circuit in males, 00:49:45.343 --> 00:49:51.923 but I wouldn't be surprised if those olfactory inputs about pup-related information 00:49:51.923 --> 00:49:57.623 were acting on that part of the circuit and inhibiting the medial preoptic area 00:49:57.623 --> 00:49:58.803 from responding to infants. 00:49:59.383 --> 00:50:03.723 And perhaps for whatever reason, under laboratory conditions, 00:50:03.723 --> 00:50:05.103 these animals are inbred. 00:50:05.163 --> 00:50:10.263 They're constantly smelling pups because usually we all, everyone's raised in 00:50:10.263 --> 00:50:14.563 the same room and it's sort of an artificial scenario. And I think that. 00:50:15.447 --> 00:50:20.947 Maybe there's some sort of habituation that has led to a downregulation of that 00:50:20.947 --> 00:50:28.587 circuit or sort of led to that circuit not being activated as much as it would have been activated. 00:50:28.867 --> 00:50:34.947 And so all you need to do then is present them with PUPs, and they're not avoiding those PUP stimuli. 00:50:35.227 --> 00:50:38.847 And so if you present them with the PUPs enough, you can get the other aspect 00:50:38.847 --> 00:50:42.247 of the circuit to increase. And so what I'm referring to here really is this 00:50:42.247 --> 00:50:48.287 approach avoidance model of the onset of maternal behavior, which has been established in rats. 00:50:48.747 --> 00:50:53.567 And the model really states that avoidance tendencies have to be decreased and 00:50:53.567 --> 00:50:55.827 approach tendencies have to be increased. 00:50:55.927 --> 00:50:58.627 And when those two lines cross, that's when you get maternal care. 00:50:58.967 --> 00:51:03.487 Right. Clear. But it also means in terms of behaviorally, these males display 00:51:03.487 --> 00:51:05.967 identical behaviors as the female rats. 00:51:06.007 --> 00:51:09.487 So including presenting themselves for feeding. 00:51:10.367 --> 00:51:14.527 Yes, they do. But I would argue that that's reflexive. You can see that in rats, too. 00:51:14.727 --> 00:51:17.867 And so all you really need for that is pups. 00:51:18.027 --> 00:51:23.387 If you orient yourself over the pups, the pups will induce you to show those crouching responses. 00:51:23.767 --> 00:51:25.827 Right. Okay. All clear. Tony? 00:51:26.207 --> 00:51:33.207 Okay. So we had now this exploration through the epigenetic landscape of maternal behavior. 00:51:34.829 --> 00:51:38.149 But what's the next step there? Where do you see this go? 00:51:38.909 --> 00:51:44.149 So there's many more questions that I'd like to explore within this particular model. 00:51:44.729 --> 00:51:49.789 And some of them I've alluded to, and particularly really defining these mechanisms. 00:51:50.409 --> 00:51:56.689 I would love to be able to look at all of the histone changes and really characterize 00:51:56.689 --> 00:52:00.909 which marks are coming up during these experiences, when they're coming up and 00:52:00.909 --> 00:52:02.069 how long they're coming up for. 00:52:02.749 --> 00:52:06.629 So one thing I should note is that epigenetic changes, while they can be stable, 00:52:06.789 --> 00:52:08.149 they can also be very dynamic. 00:52:08.289 --> 00:52:14.709 And so you can have changes in histone acetylation increasing and decreasing over a couple of hours. 00:52:15.009 --> 00:52:19.269 You can also have changes in the activity of other what I would call chromatin 00:52:19.269 --> 00:52:22.229 modifiers, so things like DNA methyltransferases. 00:52:22.409 --> 00:52:26.609 And I didn't talk about DNA methylation, but one of the things that I have found, 00:52:26.649 --> 00:52:27.769 which which I did not present today, 00:52:27.949 --> 00:52:35.029 is I found changes in the gene expression of DNMT3 with DNMT3A, 00:52:35.149 --> 00:52:40.169 which is a de novo DNA methyl transferase, meaning that it adds methyl groups 00:52:40.169 --> 00:52:42.429 that were not previously on cytosine residues. 00:52:42.689 --> 00:52:48.469 And what exactly is happening with that change in DNMT3A, 00:52:48.629 --> 00:52:53.129 I'm not entirely sure, but it would indicate that maybe there's some methylation 00:52:53.129 --> 00:53:00.769 that's being added or modified at least in these animals with experience. 00:53:00.989 --> 00:53:03.809 So I think there's a lot of mechanism that needs to be sorted out. 00:53:03.929 --> 00:53:09.069 And clearly there's some interesting behavioral experiments that I'd like to do as well. 00:53:09.269 --> 00:53:13.089 And I see some of these questions being asked in males as well. 00:53:13.469 --> 00:53:20.349 But now, so here you are, upcoming light of epigenetics, right? Right. 00:53:22.869 --> 00:53:28.929 So, but if you could now define a single law that we should follow to understand 00:53:28.929 --> 00:53:34.409 brain and behavior, what would be this Daniel Stolzenberg law? 00:53:35.989 --> 00:53:37.709 A single law? Yeah, one. 00:53:42.549 --> 00:53:45.549 I'm not sure if I understand what you mean by a single law. 00:53:45.829 --> 00:53:49.589 Well, what would you tell your students? Like you have to follow this rule to 00:53:49.589 --> 00:53:52.389 be successful so we can understand the brain. What's the one rule? 00:53:52.529 --> 00:53:55.789 What's the Daniel Stolzenberg law to understand brain and behavior? 00:53:58.460 --> 00:54:05.180 I think that it's worthwhile to investigate a natural behavior when you're interested 00:54:05.180 --> 00:54:10.260 in how the brain is regulated. So ecological validity for you would be key. Yes. 00:54:10.320 --> 00:54:12.680 Okay. And then, so Tony likes traveling. 00:54:13.480 --> 00:54:18.040 So he will come and inspect your lab four years from now. And then he's going 00:54:18.040 --> 00:54:20.060 to carry a little note that I wrote. 00:54:20.400 --> 00:54:24.680 And the note will say, look, Tony, you really have to check whether this prediction 00:54:24.680 --> 00:54:27.600 that Daniela made four years ago was really confirmed. 00:54:28.580 --> 00:54:33.120 So what's the one prediction you would like to make today that Tony can come 00:54:33.120 --> 00:54:36.440 and test to see if it actually happened four years from now? 00:54:36.700 --> 00:54:38.920 In terms of my data? Yeah, better. 00:54:41.560 --> 00:54:48.980 I think, well, the one thing that I would really like to do, 00:54:49.000 --> 00:54:51.760 as I said, is characterize these changes. 00:54:52.000 --> 00:54:55.180 But I don't want to just sort of characterize them randomly. 00:54:55.180 --> 00:55:01.000 I want to conduct a series of sequencing experiments using chromatin immunoprecipitation, 00:55:01.120 --> 00:55:04.220 the method that I talked about earlier today, where you're really, 00:55:04.380 --> 00:55:08.580 I like it because you're sort of killing two birds with one stone because you're 00:55:08.580 --> 00:55:13.660 asking not only about which epigenetic players might be involved, 00:55:13.880 --> 00:55:17.960 but you're asking about where in the genome and what genes they might be acting on. 00:55:17.960 --> 00:55:22.680 So today I showed CBP being recruited to estrogen receptor beta. 00:55:22.980 --> 00:55:30.360 But if I could ask where in the genome is CBP or acetyl H3K914, 00:55:30.580 --> 00:55:35.180 where are these marks when a female is consolidating these maternal experiences? 00:55:35.260 --> 00:55:37.940 I think that that would be a really important contribution because it would 00:55:37.940 --> 00:55:44.780 give us so much information in such a more rich and global way than what I've been able to do so far. 00:55:45.480 --> 00:55:48.240 Okay, great. Then, you know, Stilson Burke, thank you very much for this conversation. 00:55:48.660 --> 00:55:50.040 Thank you for having me. Sure. 00:55:53.653 --> 00:55:59.753 Well that was fun yeah thank you 00:55:59.753 --> 00:56:03.093 thank you i think it helped a lot to clarify things 00:56:03.093 --> 00:56:05.813 right to to also get away from this idea 00:56:05.813 --> 00:56:09.033 like oh we have this this one sort of magical cell in 00:56:09.033 --> 00:56:11.893 the thalamus and the hypothalamus and it gets 00:56:11.893 --> 00:56:15.933 switched and then it all happens right yeah definitely circuit um 00:56:15.933 --> 00:56:19.693 it's that has been very good it's it's 00:56:19.693 --> 00:56:22.413 hard to know exactly what what to 00:56:22.413 --> 00:56:25.133 present it's funny because i had all these circuit slides in and 00:56:25.133 --> 00:56:27.993 i took them all out at the last minute but um 00:56:27.993 --> 00:56:31.013 you know it it's uh i i think 00:56:31.013 --> 00:56:33.833 that um i've always really thought about 00:56:33.833 --> 00:56:37.733 things from a circuit level and it's just it's just it was very depressing to 00:56:37.733 --> 00:56:40.953 me that i could find no changes anywhere else in the circuit which is sort of 00:56:40.953 --> 00:56:45.873 what's interesting is that maybe this maternal behavior is just recruiting other 00:56:45.873 --> 00:56:47.513 behaviors and modifying them 00:56:47.513 --> 00:56:53.313 so slightly so i mean we We talked about cannibalism in various species, 00:56:53.513 --> 00:56:58.533 and the fact that monodelphus just cannibalizes its young when it doesn't recognize them. 00:56:58.713 --> 00:57:03.353 It's quite interesting, because you can imagine that the retrieval mechanism 00:57:03.353 --> 00:57:06.433 is not that different from the cannibal mechanism. 00:57:06.833 --> 00:57:10.413 I grab it, and I drag it back here, and then rather than- No, it's very different. 00:57:10.813 --> 00:57:14.153 No, Tony, there's a really important difference, because what I understood about 00:57:14.153 --> 00:57:21.373 mice, pregnant mice, because mice are living in colonies, right? 00:57:21.653 --> 00:57:25.733 And they all, the pups in the end are taken care of by all of them in some way. 00:57:25.793 --> 00:57:28.653 It's not really very specific, if I have it correctly, right? 00:57:29.213 --> 00:57:31.933 So what these mothers do, they kill the pups of other mothers, 00:57:32.093 --> 00:57:35.713 so there's more capacity for those other mothers to take care of their offspring. 00:57:37.323 --> 00:57:41.483 Okay, so the cannibalism is very specific, specifically focused. 00:57:41.563 --> 00:57:45.443 I'm not saying that they're not deliberately killing certain ones, 00:57:45.563 --> 00:57:49.083 but I'm just saying that the actual… You're saying like the actual act. 00:57:49.083 --> 00:57:52.983 The actual behavior, the sequence of actions that you do. It actually looks… 00:57:52.983 --> 00:57:55.163 It's not that different. You just have to grab a bit tighter. 00:57:55.423 --> 00:57:59.123 No, wait, I wanted to say what we call cannibalism. 00:57:59.223 --> 00:58:04.403 There are actually many different kind of sub-behaviors underneath that we should 00:58:04.403 --> 00:58:08.263 not summarize with that one word. because cannibalism might mean it's for food, 00:58:08.683 --> 00:58:13.103 it might mean maternal competition, or it might mean an accident. 00:58:13.923 --> 00:58:18.243 If we call all of this cannibalism, I think we're confusing ourselves unnecessarily. 00:58:18.403 --> 00:58:22.383 I think I'm making a different point, which is that… Look, I got to run. 00:58:22.483 --> 00:58:26.483 I'm sorry. To get maternal behavior, you don't have to evolve a whole lot of new action patterns. 00:58:26.623 --> 00:58:31.143 What you have to do is you say, well, in this context… I don't buy that at all. 00:58:31.663 --> 00:58:34.483 I don't buy that at all, and I will tell you that during our reception. 00:58:34.483 --> 00:58:37.723 Okay, we can talk later. See you later. Yeah, thanks. 00:58:38.923 --> 00:58:44.463 I might say to that point, though, Tony, that the behavior looks really different when you see it. 00:58:44.543 --> 00:58:47.123 Okay, well, I could be wrong with that example. The way that they approach the pups. 00:58:47.223 --> 00:58:50.883 But I agree with what you're saying, generally speaking, in terms of like how 00:58:50.883 --> 00:58:52.483 many behaviors does, you know. 00:58:52.623 --> 00:58:55.063 You've got to think about how you evolve internal behavior. 00:58:55.323 --> 00:59:00.783 And I don't think you evolve a complete set of new behaviors because what you 00:59:00.783 --> 00:59:03.063 can do is you can say, I've got some existing behaviors. 00:59:03.143 --> 00:59:06.243 I'm going to parameterize them so that I retrieve the pup. 00:59:06.843 --> 00:59:10.703 Normally, maybe I'm catching something, bringing it back to eat. 00:59:10.743 --> 00:59:12.523 Now I'm catching something and bringing it back to nurse. 00:59:12.663 --> 00:59:18.683 Take care, yeah. You don't have to evolve a whole new set of strategies for 00:59:18.683 --> 00:59:21.663 fetching that object back to the nest because you already know how to do that thing. 00:59:21.783 --> 00:59:25.523 I agree with that, and I would add to that point that something that's really 00:59:25.523 --> 00:59:29.243 interesting that I've wanted to look at as well that Francis –. 00:59:30.752 --> 00:59:34.612 Yeah, I think it was Francis Champagne looked at. She has this one paper about 00:59:34.612 --> 00:59:38.032 weaning, and we really know very little about weaning, and particularly in mice. 00:59:38.612 --> 00:59:44.472 And what she did was she kept these pups in the cage with the mothers after 00:59:44.472 --> 00:59:48.852 day 21, which is typical weaning time, till day 28. 00:59:48.992 --> 00:59:52.532 And what she ended up seeing, and she actually sent me the video, 00:59:52.592 --> 00:59:56.352 so I saw this in real life, even though I tried to replicate this, 00:59:56.432 --> 00:59:58.552 but I think I did some things wrong and I couldn't see it. 00:59:58.552 --> 01:00:03.132 But the females actually, as the pups get older and the females are, 01:00:03.192 --> 01:00:06.432 I'm assuming, not wanting them to nurse anymore, they actually pin the pups 01:00:06.432 --> 01:00:09.592 and they basically start thrusting against them. Right. 01:00:10.012 --> 01:00:14.292 And, I mean, it's just really bizarre. But, you know, it's sort of like we've had this conversation. 01:00:14.472 --> 01:00:18.692 And I guess it makes sense how many different behaviors, right, 01:00:18.792 --> 01:00:22.472 are available to, I think, to a mouse. 01:00:22.472 --> 01:00:25.192 Else and i think that this speaks to exactly what you're saying that 01:00:25.192 --> 01:00:28.172 you're not going to sort of evolve this new behavior to get the to 01:00:28.172 --> 01:00:31.172 sort of actively wean your offspring instead you're 01:00:31.172 --> 01:00:34.492 just going to use a behavior that you already have that clearly the pups are 01:00:34.492 --> 01:00:38.952 not going to enjoy i mean downstream i think there's an argument to be had about 01:00:38.952 --> 01:00:42.392 what how many different mechanisms there are and how you recruit different mechanisms 01:00:42.392 --> 01:00:47.592 but um you know sort of the old ethologist idea of fixed action pattern i mean 01:00:47.592 --> 01:00:49.672 it's not it's not completely right it's not 01:00:49.712 --> 01:00:52.472 completely dead either but then you can imagine you know sort 01:00:52.472 --> 01:00:55.692 of this action pattern is triggered by the stimulus i do 01:00:55.692 --> 01:00:58.432 it or i take that action pattern i change it a little bit i've 01:00:58.432 --> 01:01:02.912 got a new action pattern which does something else yeah so so i mean you what 01:01:02.912 --> 01:01:07.432 you want to say is well okay maternal behavior evolves in mammals what what 01:01:07.432 --> 01:01:11.792 has to evolve for that to take place and it it may not be that many steps away 01:01:11.792 --> 01:01:17.252 from what you can already do uh as a reptile but certain Certain things obviously have to change. 01:01:17.392 --> 01:01:25.112 But in animal-like monodulphus domestica, you can see that it's fairly crude. 01:01:25.232 --> 01:01:32.012 So that whether it nurses or cannibalizes an infant is based on possibly a single 01:01:32.012 --> 01:01:33.372 cue, whether it smells right. 01:01:34.052 --> 01:01:38.232 Yes. And yeah, I think absolutely. I think absolutely that's involved. 01:01:39.272 --> 01:01:41.212 Anyway, thank you very much. Thank you. 01:01:42.892 --> 01:01:48.732 So now you can relax. Oh, you have another tutorial? The CSN podcast was produced 01:01:48.732 --> 01:01:53.212 by the Convergent Science Network of Biometrics and Biohybrid Systems, 01:01:53.492 --> 01:01:58.372 a project funded by the European 7th Research Framework Program. 01:02:00.400 --> 01:02:26.768 Music.