Episode 11: Jumpstart Your Career (Transcript)

Peter 0:12
Hi, and welcome back to The Gastronauts Podcast. My name is Peter and I’ll be your host. Here at Gastronauts we are committed to exploring communication throughout the body, with a particular focus on the crosstalk between gut and brain. We invite experts in this field to share both their research and their incredible journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts podcast.

Today, we have a double-header, we have two young scientists who are rising stars in their field. First up, we have Dr. Natale Sciolino, who is a postdoctoral fellow at the developmental neurobiology group at the National Institutes of Environmental Health Sciences in Dr. Patricia Jensen’s lab. She completed her PhD in Dr. Phillip Holmes lab at the University of Georgia, where she studied the effects of voluntary exercise in preventing cocaine relapse. She is currently studying the role of norepinephrine neurons in the locus coeruleus. These neurons are traditionally thought to be involved in that fight-or-flight response and related to these stress or panic like situations. But Dr. Sciolino has uncovered some interesting results that they may also play a role in feeding behavior. So could you tell us a little bit more about this project and how you stumbled into this field from going into a research field to begin with?

Dr. Sciolino 1:58
Yeah. So the thing that’s always fascinated me is how does the brain form emotions and then take those complex internal states and integrate them with essential needs like hunger to then drive motivated behavior of an animal. Because all the things that we do are not happening in isolation. All of these internal states work together in concert, and the brain must decide what gets priority. So to me that orchestration is the most interesting. And it turns out, as you said, the neurons that orchestrate the fight-or-flight response, actually do much more in that coordination. They also tap into other internal needs, like relaying information about hunger or feeding. So what I’m talking about is the locus coeruleus. So the locus coeruleus is the largest grouping of norepinephrine containing neurons in the brain. These neurons actively synthesize the neurotransmitter norepinephrine. But they have diverse projections all throughout the brain. And that’s how come the neurons are able to modulate a variety of processes in the brain. So they’re implicated in emotion regulation, stress responses, cognition, arousal, sleep wake, the list goes on and on and on. And we’ve uncovered they also play a role in modulating feeding. So how does this transmitter system do all of these things? And it turns out, it does so many things through circuit-specific projections throughout the brain. And really, what we think the system is doing is turning up the gain and neural networks to say, “okay, this is the priority right now based on my internal state or the environment […] well, I’m full, there’s no predator around. I can work on cognition; I can focus my efforts towards that. So I want to turn up the gain if I’m norepinephrine in cognitive circuits.” Whereas say there was a predator around and you have to run for your life, I want to turn up the gain and my stress responsive centers to get away from that predator. If you were to think of it as a radio dial, right? But you have that radio dial not on one particular channel, but you have this Master Control Center, where you have radio dials on a bunch of stations, and you’re turning up those radio dials to see what kind of signals you want to listen to, on these different channels.

Peter 4:47
So how does the stress feed into this circuit? To my understanding what you’ve described so far is, once you’ve had this stressful state, you can affect the game based off of norepinephrine, but how does the stress get into the circuit to begin with?

Dr. Sciolino 5:00
Yeah, so good question. So I think a lot of it has to do with what the level of activity is in locus coeruleus neurons. So we know stress classically, can cause this robust activation of locus coeruleus neurons. Whereas other things, let’s say appetitive things that are rewarding, unpleasant, like feeding, cause the opposite change, a decrease in locus coeruleus activity. And that magnitude of effect of just endogenous eating is small when you talk about every bite by bite effects. So we have all of these, all of these ways that our behaviors can change locus coeruleus activity.

Peter 5:44
That’s really neat. And do we have an idea of kind of where the locus coeruleus projects to, to control feeding or to control these different responses?

Dr. Sciolino 5:53
Yeah, so we’ve identified a circuit in the brain; probably, there’s many more But there’s a projection from locus release to lateral hypothalamus that suppresses feeding. And it also induces a negative emotional state, so characteristic of an anxiety-like response, if you will. And it’s aversive. So this is just one circuit that we’ve identified, but there may be others.

Peter 6:21
Do you think there’s a way to uncouple the anxiety effect with the feeding behavior? Do you think those two go hand in hand?

Dr. Sciolino 6:27
I think it’s probably projection specific, or if not projection-specific, cell type specific at the target. I think that there probably is a way to uncouple the anxiety and feeding. And the reason why is because a lot of beauty in science comes from just observing. And so one really cool observation that we found is when we just looked at natural endogenous activity of locus coeruleus neurons. When animals are eating, we found that there’s this dynamic change in activity during feeding and local coeruleus activity. So here’s the dynamicness, when you approach food, you have this sharp rise in locus coeruleus activity. And when you consume food, you have a smaller decrease in activity. So you have two different processes that are happening. And both of those processes are modulated by how hungry you are. So if you’re less hungry, both responses are attenuated. And so they’re looking at endogenous activity. And this is just speculation, but if I were to guess, I don’t think that they’re having moment-to-moment instant changes in anxiety. I think probably what’s going on, there are the subtle changes in arousal or salience. And so perhaps, if that’s true, the circuits that are mediating those food related changes in locus coeruleus activity and changes in arousal or salience those may not be anxiety dependent.

Peter 8:01
So that’s how you think about kind of teasing apart the two effects? Really interesting. And then your previous work was on the effects of exercise and preventing relapse from cocaine. How do you see that work related to the work that you’re doing? Now, I know you mentioned you’re very interested in these physiologic states and [during your] postdoctoral training was there something in particular a field in particular or type of environment that you’re looking for in particular, to move you towards this direction?

Dr. Sciolino 8:30
Yeah. So it all falls within the umbrella of what is motivated behavior. So motivated behavior, simply put, is the ability to seek pleasure or to avoid harm. And we have adaptive processes set in place in the brain to allow us to fulfill those two motivated behaviors, right? So to seek pleasure, you know, we seek out food, but there can be maladaptation in those processes, leading to, let’s say, drug addiction. So it’s just I guess, a dysfunction versus an adaptive behavior, but it’s all looking at the same, probably tapping into similar circuitry and mechanisms.

Peter 9:15
Was the locus coeruleus involved at all in the exercise?

Dr. Sciolino 9:18
Yeah, it turns out if you run a lot, you see this up-regulation of a growth factor or a trophic factor called galanin. And it’s only in one brain region. The locus coeruleus is, you don’t see it and other galanin-expressing neurons in the brain. Exercise selectively dramatically up-regulates this trophic factor glanin. The work I did as a PhD student and Phil Holmes lab was really trying to understand what galanin was doing in the locus coeruleus, in terms of how it would affect the function of locos coeruleus in terms of its chemical functions, structural changes, as well as its behavioral effects. And we found out that galanin is necessary and sufficient for promoting resilience to stress. Because when you exercise, you’re very resilient to stress. And those changes are mediated by gallon.

Peter 10:21
And do you feel like galanin will also have any influences on kind of the norepinephrine gating of appetitive behavior?

Dr. Sciolino 10:29
Yeah, that’s a really cool question. I don’t see why not. Yeah, but we haven’t looked at that. Yeah, that’s a really cool question.

Peter 10:38
Well, I’m excited to see what comes out of that. You were recently awarded a K99 from the NIH, and congratulations on that. For those who are not familiar with the term of the K99, it’s a grant that will allow you to transition to starting your own laboratory. Now that you’ve gone through the process, I was wondering if you have any advice for others, looking to apply For this award or something that you felt was really helpful for your application.

Dr. Sciolino 11:06
I’m trying to decide if I want to give the true answer or the polished answer. I’ll first give the polished answer. The polished answer is: submit. Even if you think you’re not ready, because I think that oftentimes we are our own gatekeepers, and we can be the hardest on ourselves. So get over that if that’s something that you’re struggling with. And then number two, have it be as polished as it can be, have multiple people look at your application materials and critique it. I think I spent probably, like literally months on just my specific aims page. And then soon as I figured out what the aims would be, then the rest kind of followed suit, but leave a lot of time to work and edit. My first time, I was reviewed on the first submission and I received an OK score, not fundable. And then the second time I received a perfect score. And I think that has a lot to do with the fact that I revised a lot, and had the opportunity to bounce my ideas off of multiple people. So I think that’s really important. And I tried that, and it’s well, I got I was funded by an institute that only awards 1 K99 a year. So the odds were stacked against me. So maybe for me, it was more important to really have a polished application whereas other institutes that say fund 50%, maybe that’s less important. So inherent in that processes, know your institute and your odds.

Peter 12:44
Was that your polished answer your real answer-

Dr. Sciolino 12:48
The real answer is polish the turd. And that is like: a lot of things in science don’t work out. So how to spin your experience and you know, your failed experiments, and all of these things together as one uniform logical flow. And I think that the answer always is polish the turd.

Peter 13:18
So what was the turd that you’re polishing? I know briefly we have talked about your view of these locus coeruleus neurons, or these norepinephrine neurons within the locus are really just tuning [the gain]. How you go about testing this?

Dr. Sciolino 13:30
Yeah, so for me, it was more, it was a really big challenge to get up fiber photometry in the locus coeruleus. And I thought photometry is so it’s a way to measure endogenous activity of neuronal cell types. And I study a really hard area to target and study in the brain the hindbrain: the locus coeruleus. And so for me, my thing that I had to polish was really gaining access to that cell type in a reliable way so that we could trust the data. And so that took me a really long time to do. And so you know, that first submission, what I had was proof of principle that I could record from that cell type. And you know, that’s good enough. Like it wasn’t the inherent answer to the question. But I overcame that hurdle. And that was what I presented as a strong point. And by the time I had the second revision, I actually had real data to support the underlying hypothesis of my research.

Peter 14:34
Yeah, that’s neat. So then you were able to measure the changes. You mentioned that when these mice moved closer, or when they started approaching food, you saw a spike in these norepinephrine neurons, but then as they started consuming it, they had a decrease in activity and that was measured through this fiber photometry. What do you see this technique being used for expanding upon that research?

Dr. Sciolino 14:59
Basically, fiber photometry is really great for recording from deep brain structures. However, what it is not good at is defining cellular resolution. So what you’re recording is actually a population of neurons. So if, let’s say, the neural signatures that we just described, and the locus coeruleus neurons are only mediated by, I don’t know, a third of the cells, then the response, let’s say, when you record in the population might look entirely different than if you were to record from that third of the population. So I would say that the next steps are getting at subpopulations and really identifying the neural source. And then once we do identify the causality, are they causally linked to the changes in behavior?

Peter 15:52
Do you have aspirations in your lab to potentially silence these specific norepinephrine neurons and look at whether or not you can modulate their stress levels and their consumption?

Dr. Sciolino 16:03
Right, and in a very temporally specific manner.

Peter 16:07
That’s really cool. I can’t wait to see what you find out. I wanted to take kind of a step backwards, even before you started doing this type of research. When you were transitioning from a grad student to a postdoc position, how did you decide to pick the NIH versus any other academic institution?

Dr. Sciolino 16:25
What I really like about being in the intramural program at the NIH, is that we have all kinds of incredible resources. And that resource comes in the flavor of money to buy reagents or equipment, but also people and that’s probably where it shines the most. So we have phenomenal cores and staff scientists and postdocs and post backs, and all are very skilled. And because the PI’s don’t have to write grants, they’re more in the lab and to me I saw that as a huge strength to be a postdoc in that kind of environment. Because you can work one on one with the expert in in whichever be that a PI or the head of a core of an imaging core say, for example, or are really phenomenal neuro-behavioral core

Peter 17:19
And then one last question I wanted to ask was mostly focused on where you see the field moving forward with regards to the involvement of norepinephrine in feeding, or is there even a field for this? Are you pioneering this field to begin with?

Dr. Sciolino 17:35
Yeah, I think what this argues is it supports the work of many people in the field. Basically, newer work is showing that there’s a lot of diversity and the noradrenergic system. Previously, the idea was that the noradrenergic system is just, you know, this pretty homogenous neuromodulatory system that is acting at multiple places all at once. And it’s basically just turning up the gain of function of multiple neural networks. But I think what we’re learning is that there’s a lot of diversity in terms of projection specific functions, or molecular diversity or genetic or developmental diversity in the system. And once we uncover that diversity, we can really link it to complex behaviors. So I think that my research fits within that framework. And that locus coeruleus neurons are doing diverse functions, one of which includes feeding and modulation.

Peter 18:39
Do you feel like […] the fact that current complex behaviors haven’t been modulated specifically by targeting this homogenous population that we haven’t appreciated the diversity for- so ultimately, do you feel that by getting to the crux of the diversity within kind of norepinephrine cells or cells that we’ve classified as a particular subtype we’ll be able to really treat or modulate complex behaviors.

Dr. Sciolino 19:05
Yeah, I think that that’s, that’s one way to get out. And and that’s where the latest advances and tools currently allow us to get out.

Peter 19:15
Yeah, I think like a lot of the technology that we’ve seen has been, at least with the development of technology, we’ve seen more finer and finer kind of granulation of cell types of tissue of anything in general. And do you think there will reach a point where we continue to look at each of these individual cells and then continue to, break them down into smaller and smaller parts- do you think there will be a point where we’re going too deep, and that we won’t be able to see a large behavioral response by targeting kind of a sub population of a sub population of cells?

Dr. Sciolino 19:49
Yeah, I don’t know. I guess it’s all worth studying. And I think I use behavior as that readout of whether something is functionally important, right? So that’s that’s how I see behavior as a way to ground, whatever you’re studying. And its basic relevance, not to say that things that don’t change behavior are not relevant. But of all the things to study and there are so many, that’s just the way that I make my decisions.

Peter 20:19
It’s a very important readout, right? If we see a change in a protein, we don’t know what this affects in the animal or in the human in the long term. Yeah. Well, thank you so much for sharing some of your thoughts and ideas with us.

Dr. Sciolino 20:31
Yeah, thank you for having me. This was fun.

Peter 20:52
We also have Dr. Sophia Axelrod here with us today. She is a postdoctoral researcher at Rockefeller University in Dr. Michael Young’s lab. Her current research focuses on how circadian rhythms work and what physiologic or homeostatic processes are regulated by our circadian rhythms. We were just talking a little bit beforehand and I wanted to ask her a little bit about her career development or career path coming to this postdoctoral position, and trying to find out where she was doing her PhD, but had some difficulty researching this. So I just wanted her to share some of her story.

Dr. Axelrod 21:28
Happy to be here. Thank you. And yeah, I think when I was, you know, an undergrad, I had two main areas of research interests and those were immunology and the nervous system. And I did the immunology part first, but then I wanted to switch to neuroscience and from my PhD, I joined a lab at Rockefeller with Ulrike Gaul and she studied developmental neurogenetics, so how are genes affecting development of the nervous system. And specifically, we were interested in glia. So it was actually glial phagocytosis apoptotic cells that means, how do glia remove dying neurons during development?

Peter 22:15
Because our brain produces an excess of neurons.

Dr. Axelrod 22:18
That’s right. And that was also the connection to the immunology thing I did before, because in my undergrad, I studied how macrophages eat tuberculosis bacteria. So I came from infection biology, where I studied phagocytosis of bacteria. And then I switched to neurodevelopment where I studied how glia eat dying neurons. And then for my postdoctoral work, I wanted to do adult behavior. I had seen a couple of talks where people study behavior in flies, and I thought that was preposterous that you would even you know, consider doing that but you can figure out so many things about it in flies that I thought, “yeah, why not stick with the, with the fly.” Ultimately, all behaviors are, you know, we all have to achieve the same stuff.” Whether we are fruit fly or a person, we have to find the food, we have to avoid dangerous stuff and we have to find a mate. And we don’t know how it works in any organism. So we might as well study it in something simple.

Peter 23:20
So the transition from development to adult behavior, was that kind of an organic process for you? Did you have to tell yourself, oh, I’m not going to be a developmental neuroscientist anymore? Or is that something that you’re still thinking is part of where you want your career moving forward?

Dr. Axelrod 23:37
So there is actually a development aspect in my story here. You know, in my postdoctoral work, it’s just, you know, that there is something like developmental contributions to adult behavior, obviously. And I’m not excluding it for the future. The transition was pretty smooth, because, you know, we’re all such specialists anyway, and the focus really in my lab, like it in Ulrike’s lab is a genetics. And so if you if you think from a genetic perspective, it doesn’t matter what the actual assay is, whether it’s like, looking at macrophages in the embryo or looking at sleep in the adult, you know, you’re knocking out genes in certain cells, and you look at the contribution of these cells to whatever your phenotype is. So it’s not you, of course, you need to understand a lot of new stuff, but it’s not that different to me whether it would be a different topic in developmental biology versus just switching to adult behavior.

Peter 24:30
So just understanding how the genes interplay [and] the programming of the biology in the cell types as opposed to what the readout is. Yeah. Okay. Really interesting. And now your current work really focuses on circadian rhythms. And you mentioned you’re interested in an array of physiological behaviors. Can you tell me what roles the circadian rhythms play in governing different types of behavior?

Dr. Axelrod 24:54
Yes, um, it’s kind of shocking actually. Pretty much anything you can think of is circadianly regulated not just when we sleep, that’s the most obvious thing, right? Like, the timing of sleep is regulated by circadian rhythms, but also things like your body temperature, your bowel movements, but also your mood, alertness. Any hormone you can think of, any physiological parameter that has been tested, almost any logic parameter is circadian regulated. It’s like a bead of strings that exists to optimize processes in our body. And we’re not even aware of it.

Peter 25:33
And other particular behaviors or actions that you’re looking to read out from the circadian rhythms. And let me take a step back- a circadian rhythm is an internal clock within yourself that correct kind of something that has a certain sense of timing throughout the day.

Dr. Axelrod 25:47
Right. So the definition of a circadian rhythm means that it’s a physiological parameter or a behavior that takes about a day- circadia means about a day. And there’s another actually aspect to the definition and that is that it has to be entrainable, entrainable to a so called zeitgeber, a time cue, the most famous zeitgebber is light. But the big focus of the field is right now uncovering other time cues. Like for example, food, food is another zeitgeiber. But all kinds of things can be zeitgebers. In fact, you can think of it as anything you do or don’t do at a certain time of day might be a zeitgeber.

Peter 26:23
So we have these intrinsic clocks that can also be governed by kind of environmental cues such as light or food or whatnot. And if the cues are discordant, say like, you go on a flight, right, and you have jet lag, and your cues are discordant is the one that wins out if your environmental cues are very different than your kind of molecular clocks. How does your body resolve this?

Dr. Axelrod 26:45
Yeah, that’s a good question. So when you go on a trip, and the light input starts conflicting with your inner clock, what happens is that the amplitude of your circadian rhythm just breaks and there is a phase reset going on. And that takes a few days and then you were back on track with the new timezone. If you create a conflict between, for example, different zeitgebers. So you eat out of sync with your food, that’s actually fine. And you will have split rhythms in your body, like your brain can be on one timezone. And your liver can be on another one.

Peter 27:22
What effects will that have if your brain and your liver functioning on different time scales?

Dr. Axelrod 27:27
So that’s actually not a big problem probably as long as it’s regular. So I feel like there’s a big thing in the field right now. It’s called time-restricted eating, or feeding, where you don’t eat at certain times of the day, and then your liver clock is probably going to be entrained to a phase shift to your light input. If you don’t eat, for example, for the first six hours or so of your wake time, but as long as you do this every single day, there are no negative effect. And in fact, we know that time-restricted feeding has a lot of health benefits. So like everything with rhythms, it’s important to repeat it all the time.

Peter 28:02
certainly. And these rhythms govern pretty much all of our biology, and I was wondering, are you focusing on any particular biology in particular? Or do you care about all of these different physiological behaviors that are regulated by the circadian rhythm?

Dr. Axelrod 28:16
So what I wanted to actually work on was sleep when I came to the lab, because sleep independently of rhythms is kind of an enigma. We don’t really understand the function of it still; some people think it’s one of the big frontiers in science. So a lot of basic research is focused in you know, in the field is trying to understand why we sleep, what happens to the cells in our body when we sleep, and why is it so bad if we don’t sleep? And do other animals sleep the same way that humans sleep? No, in fact, our sleep is pretty unusual, and that is so consolidated, most animals nap, including fruit flies. So sleep and most animals have a circadian rhythmicity but it’s still much more fragmented than in humans. Almost no animal sleeps in one block. And also the amount of sleep is vastly different across the animal kingdom. And there are theories about what that means, and how we can use that information to understand what sleep is. But basically what I wanted to know when I came to the lab is how glia affect circadian rhythms and sleep. And what I found was that there is this thing called the blood brain barrier that is basically like a protective membrane or protective layer around the brain to ensure that in the brain, you have very specific, a very specific micro environment, so that neurons can function. And I found out that this barrier is actually not always closed and that that barrier opens and closes and that has something to do asleep. So that’s what I work on. So no, I don’t work at all on all aspects of circadian biology. I try to say it’s a huge, huge field.

Peter 29:55
Interesting. Could you tell us a little bit more about this blood brain barrier membrane changing with regards to sleep. Are you saying that if you sleep more, is there a a stronger membrane or a stronger barrier? Is it the fact that the barrier changes its integrity? Or is it the fact that the barrier kind of moves?

Dr. Axelrod 30:14
So yeah, that’s exactly what I found. I found that if you don’t sleep, the BBB, the blood brain barrier, it kind of breaks down and it’s, it’s the tight junctions, it’s the the proteins that are between the cells that form the barrier. It’s like a diffusion barrier. It doesn’t let anything through. It’s like it looks on the electron-microscopy looks like a ladder. And this ladder protects the brain because stuff just can’t get through. But when you don’t sleep, the ladder breaks a little bit. And when you then catch up on sleep, it closes again. That’s what it found. And that’s kind of unusual. I mean, it’s kind of unexpected, because we thought the BBB is static. We thought it just has to be made and it has to stay in place. And that’s that and I don’t think that’s the case. And that has all kinds of interesting implications.

Peter 31:02
Yeah, that’s really neat. I was wondering, why do you think the blood brain barrier changes with regards to lack of sleep? Do you think it’s perhaps because you’re not getting enough sleep? Your brain thinks that, oh, maybe I need to grab something else from the bloodstream?

Dr. Axelrod 31:15
Yeah, that’s the million dollar question, at least in my mind: what is actually going through? And what is the body trying to achieve? I do think that it is trying to do something, I think this isn’t some kind of adaptive response. I don’t think it’s actually breaking because I know that it closes really quickly again. So I think it’s trying to accomplish something, either letting something get out or letting something get in. And I don’t know what that is. But of course, I thought about what it could be. And there is, of course, a number of things that are asymmetrically distributed across the blood brain barrier. That is why we have it in the first place, right? And one of the most basic things that is that has a differential is our ions, the ion concentration, for example, potassium is very different in the blood than from the brain and you could actually say that opening the BBB just a little bit would allow ions to flow according to their concentration gradient. And then you could imagine how that could affect globally neuronal excitability in the brain. In fact, that has been shown in, in […] lab a few years ago there across the wake states, you see changes in ionic concentrations outside of neurons, but they don’t know where that comes from. So I still don’t know where it comes from. But it could be the BBB that allows those changes. And then that could be a mechanism to quickly switch from asleep into an awake brain. Because that’s what we experience right when we fall asleep, our arousal threshold is higher, clearly something changes in a pretty profound level about the way you know how arousal the whole brain is. So you know, this could be how-

Peter 32:49
Sorry I must have missed something. Did you say that when you’re going from a sleep state to waking up your blood brain barrier changes as well or is that only over time, in a sleep deprived state.

Dr. Axelrod 33:02
So I’ve done both experiments. I’ve just, I’ve just looked at the blood brain barrier in its natural state. And what I’ve done over over 24 hours, and I see that there is a change in the permeability of the blood brain barrier. And that change is very subtle. It took me years to figure out that it actually happens. But when you then sleep deprived an animal, then there is a big change, and it really breaks down.

Peter 33:26
That’s really interesting. What comes to my mind is whether or not there’s a circadian factor or some. So we talk about these light entrainment cues, whether or not there’s a cue within the bloodstream that helps to regulate your circadian rhythms.

Dr. Axelrod 33:38
Yeah, that’s an interesting question, because I actually have a second project that is about this time restricted feeding that I mentioned before, and there you definitely are taking up stuff, right, taking up food at different times a day or not. And what we tried to understand is whether this helps the animal’s health. So we know already that time restricted feeding is really beneficial, but we wanted to know the ultimate question: does it help you live longer and it is it actually dependent on a functioning circadian clock. So if you are arhythmic and you don’t know what time of day it is because you have you know, mutations in and clock genes, then it’s not beneficial which suggests that it acts like a like a time cue at certain times of day that really helps you have a really good rhythm and at other times of the day you don’t eat your body maybe can do other stuff. For example, repair itself versus if you eat all the time. You’re just in this constant state of digestion, which is not good. And here what I also saw that the BBB is actually normally degrades over time and is actually not degrading as much when you have this time restricted feeding that helps you with your longevity.

Peter 34:41
So how long over the course of time does your blood brain barrier degrade? Is it over the course of months, years?

Dr. Axelrod 34:50
So for flies, they live only about three months which is why we can do this these longevity experiments directly. In there, you can see that in old flies, the BBB gets leakier, so it means about like halfway through their lifespan. In humans, it’s different and actually blood brain barrier degeneration is a hallmark of almost all neurodegenerative disorders. But nobody really understands what that means is that cause or effect. And I should mention that many of these [individuals] also have sleep problems. So there are these three areas: age, neurodegeneration, blood brain barrier and sleep problems. And if my findings from flies are true in humans, then they might not just be correlated, but actually causally linked to each other.

Peter 35:35
Yeah, that’s really neat. When you’re talking about extending the lifespan width time restricted feeding, one of the other studies that I know that has been done to really understand kind of dietary interventions to extend lifespan is caloric restriction. Do you think there’s any interplay between the time restricted feeding and the caloric restriction feeding?

Dr. Axelrod 35:54
So that was a major question. Of course we had, are we […] just doing caloric restriction? So we did assays where we watch how much they eat, and they actually eat more in those 12 hours than the animals that eat for 24 hours. So it’s not that, which is good, because it means it’s a distinct mechanism from caloric restriction.

Peter 36:15
So if you could calorically restrict and time restrict, would that extend lifespan even further?

Dr. Axelrod 36:20
So we did that too. And it seems like there’s an additive effect, which also speaks to the fact that those effects are different. And, yeah, it’s pretty, it’s pretty strong effects, actually, in those flies. And they were actually so strong that I started doing it myself, time restricted feeding.

Peter 36:40
It’s very popular, very popular, and-

Dr. Axelrod 36:41
it’s really easy for me, I always skip breakfast. So it’s just like, yeah, I’m gonna live longer.

Peter 36:46
It’s really interesting, right? Because people always say, you know, breakfast is the most important meal of the night. True.

Dr. Axelrod 36:52
Yeah, yeah. There’s this concept of like grazing, having like five meals a day. That’s not what we think. We think you really want to partition these activities, so that your body is not constantly burning fuel.

Peter 37:06
I think from an evolutionary perspective, right, because of the abundance of food now, it’s very easy. But if you thought about like when we were kind of a hunter/gatherer society and we had to go hunt for food, I don’t think we would eat or have these grazing properties. And I wonder whether or not our circadian rhythms are more in tune back then than they are now.

Dr. Axelrod 37:24
Yeah, there is also just the light. You know, people used to spend a lot of time outside and we don’t know we have lighting inside, but the light outside is way, way stronger. And we just don’t sense it. And because we don’t sense it, we don’t think it’s important. But our circadian system senses it very well. You know, the cells in the back of our eyes that react to the blue light, which resets our circadian clock. They respond to light exactly in the in the intensity that it is presented to our eyes. And so by being indoors a lot, our circadian rhythm is dampened a lot. There are studies that show that just a weekend Camping really boosts your melatonin rhythm, which helps you sleep.

Peter 38:06
Yeah, that’s really interesting, because we talked about all this time restricted feeding on extending lifespan. But what about kind of governing the light that you get every day and whether or not that has an impact on your overall lifespan? So making sure that[we] don’t get too much artificial light, is that been shown as to have an effect on lifespan as well?

Dr. Axelrod 38:26
Yeah. So there’s this cool question about why have circadian rhythms at all. And some of the experiments that have been done are, for example, constantly shifting your light/dark schedule, or having you in constant conditions and constant light conditions, which fruit flies, for example, and that definitely shortens your lifespan.

Peter 38:46
So there’s like an ideal amount of light and an ideal time to eat and there’s all of this will help to kind of cue our body to the best physiological state. Yeah, it’s really interesting. I want to transition a little bit to kind of the fact that you have (or) are in the process of publishing a book?

Dr. Axelrod 39:02
Yeah, it’s actually available for pre ordering. And it comes out in bookstores in May.

Peter 39:07
Amazing. And the book is on how babies sleep. And I was wondering, a why publish a book and then, what was kind of the motivation behind that, as we typically want to publish articles? What made you decide to go ahead and publish a book for general public?

Dr. Axelrod 39:24
Yeah, it’s a good question because I was actually always someone who really did not was not interested in translational things at all. I was always someone who almost prided myself in thinking I want to understand like basic principles of biology, I don’t care if there’s any applications to human health. But I just landed in the lab where, you know, it’s kind of unusual for a field like circadian biology is that it goes from you know, molecular genetics and fruit flies to human health, literally in one step. That’s that’s very unusual. And so when when you don’t want your mice to To wake up you have these special red filters in the in the door and you have this red light if you have to open the incubator at night. We have the same thing for our fruit flies. We have these dark incubators and if we have to handle the flies, we have red torches. So when my first baby was born, I was like, why I remember not using red light bulbs at night because you know when I have to go and feed her or when I have to change her diaper. I know that any light but red light will affect her melatonin, her sleep, everything.

Peter 40:30
We do that for our experiments.

Dr. Axelrod 40:31
Why not do it for our babies? So I exchanged all the lightbulbs to red bulbs. So of course it works, it’s known that this is our biology. And then there’s other things. What else do I know to help my baby sleep? I use to be a bad sleeper, so for me the biggest biggest fear was that when I have kids, I’ll never get sleep again. So I used everything that I had to help them sleep at night and then it all kind of works, which is in a way it’s not that surprising. And I need to write it down, so I remember just for myself, so I remember what I did exactly if I have another kid, I know what worked. And then it just became more and more and eventually became a book and I thought, it’ll be a book that I’ll self-publish or whatever, and I talked to a couple people and there was a lot of interest and here we are.

Peter 41:25
That’s really cool. Something that I realized was that I’m very early in my graduate career, but the things that we do in science definitely have an impact on our daily life. I’m currently doing research on how amino acids are sensed in the gut and I’m definitely thinking about how many amino acids that I’m taking in and what is the food composition. It’s really nice to see that you’ve taken the information you’ve felt you’ve gotten from your day to day research and shared that with other people and I think that’s really neat. I think that should be more in science. I’m sure there are people who are making discoveries and implementing them, maybe not to the degree that you are with circadian rhythms, but at least impacting how they make life decisions on a day-to-day basis.

Dr. Axelrod 42:02
Yeah, you should write a book.

Peter 42:04
I don’t know if I’m there yet, but definitely something to consider. I was wondering now that you have this really good understanding of circadian rhythms and how they can be applied to modifying our sleep and extending our lifespan. Where do you see your research moving forward from this as you plan to potentially start your own lab?

Dr. Axelrod 42:29
I’ve thought about this a lot this year as I was writing research statements and I tried to think where I want to take all of this. I’m lucky because this whole blood brain barrier can go in many different directions as well as time restricted feeding and there’s also intersections between these projects. But one thing I was interested in, apart from the very hard question of how it actually works or what is exchanged? We touched on each of these things as a graduate student working on their post-doc. But something I was also interested in is, is this true in mice and mammmals? If it’s true, maybe our blood brain barrier also not static? I started collaborating with mouse researchers and there seems to be indications that this is true as well. So something that I’m trying to decide is if I want to, in the future, do I want a lab that also does mouse work, because it’d be fun to bridge those two model systems.

Peter 43:26
I think that’d be really exciting and I can’t wait to see what you come up with.

Dr. Axelrod 43:30
Thank you.

Peter 43:31
I want to thank you so much for your time.

Peter 43:42
Dr. Sciolino and Dr. Axelrod shared with us two different paths to being a successful researcher. What I really want to emphasize is the importance of taking that first step. Don’t take too much time deliberating your ideas. Go ahead and write it down, pitch it to others, and polish it. If there’s something you don’t quite understand something about your daily routine, think about why. Don’t brush the thought aside and see if you can integrate this thought into a research question. The first step is often very daunting, but constantly pushing ourselves to put our foot down is the quickest way to progress forward in science. I want to thank you all so much for listening, and we’ll see you next time. For more of our content, you can follow us on Twitter @gutbrains or visit our website at thinkgastronauts.com. The Gastronauts Podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and theme music composer. And special thanks to the founders of Gastronauts, Dr. Diego Bohórquez, and the Bohórquez laboratory.