Latest / From Our Neurons to Yours / Is chronic fatigue a gut-brain reflex? (Big Ideas in Neuroscience) | Julia Kaltschmidt

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Is chronic fatigue a gut-brain reflex? (Big Ideas in Neuroscience) | Julia Kaltschmidt · From Our Neurons to Yours

• 0:10
  SPEAKER_02: This is From Our Neurons to Yours, a podcast from the Wu Sai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science.
• 0:20
  SPEAKER_02: I'm your host, Nicholas Weiler.
• 0:26
  SPEAKER_02: You know that feeling when you're pinned to the bed with the flu?
• 0:29
  SPEAKER_02: No energy to get up, get dressed, or even really think a thought.
• 0:34
  SPEAKER_02: It turns out that experience, as miserable as it is, may actually be your brain doing something purposeful.
• 0:42
  SPEAKER_02: What we're learning is that this kind of fatigue looks a lot like a reflex, a coordinated response that your body has evolved to help you recover.
• 0:53
  SPEAKER_02: But exactly how that reflex works, what triggers it in the body when we're sick, and where it lives in the brain, is largely unknown.
• 1:03
  SPEAKER_02: This response to sickness and how it produces fatigue is particularly important as we've come to realize the prevalence of chronic fatigue disorders, things like long COVID.
• 1:14
  SPEAKER_02: It's become increasingly clear these can emerge following many kinds of viral infections.
• 1:20
  SPEAKER_02: And if we want to know how to treat them, we need to know where they come from.
• 1:25
  SPEAKER_02: A new Big Ideas in Neuroscience project aims to answer these questions by mapping out how our bodies and brains communicate when we're sick.
• 1:34
  SPEAKER_02: In addition to the basic science knowledge, the researchers hope that eventually this understanding will help us detect and treat chronic fatigue syndromes.
• 1:44
  SPEAKER_02: Today's guest, Julia Kaltschmidt, is a faculty scholar here at the Wu-Sai Neurosciences Institute at Stanford, and a professor of neurosurgery at Stanford Medicine.
• 1:54
  SPEAKER_02: She's leading this project alongside Luis de Licea, who studies the brain circuitry of sleep, and Christophe Theiss, an expert on communications between the body and the brain.
• 2:04
  SPEAKER_02: Julia comes to this project as an expert on the enteric nervous system, basically the nervous system of the gut.
• 2:11
  SPEAKER_02: So I started by asking her about one of our favorite topics: why people have called the enteric nervous system our second brain, and whether that name actually does it justice.
• 2:29
  SPEAKER_02: I want to start by talking about a big picture question.
• 2:33
  SPEAKER_02: We've talked before a little bit about the gut as the second brain.
• 2:37
  SPEAKER_02: This is the title of our last conversation.
• 2:39
  SPEAKER_02: But I wanted to come back to it.
• 2:41
  SPEAKER_02: Why do people say that?
• 2:42
  SPEAKER_02: Is it just the sheer number of neurons in our guts?
• 2:45
  SPEAKER_02: Or is there are they doing something more sophisticated that feels brainy?
• 2:49
  SPEAKER_00: Clearly, okay.
• 2:49
  SPEAKER_00: So clearly there are a lot of uh neurons.
• 2:52
  SPEAKER_00: There are 200 to 600 million neurons, just to sort of get the a number on the amount of neurons, uh, which you know, if you compare it to something like the spinal cord, uh, it's more than those that reside within the spinal cord.
• 3:04
  SPEAKER_00: Um, and it's really a um call it a semi-independent neural network.
• 3:09
  SPEAKER_00: Um and I think um if you think about the brain as having particular components, like you know, you have the neurons, you have a circuit, uh, you have lots of circuits, in fact, um you have signal molecules, uh, and then sort of a communication perspective.
• 3:26
  SPEAKER_00: And so if you think about these three different maybe perspectives, the enteric nervous system um also has them, right?
• 3:33
  SPEAKER_00: So uh there are sensory neurons, motor neurons, interneurons in the uh enteric nervous system.
• 3:38
  SPEAKER_00: So there is, you know, they they form contacts and they're built circuits.
• 3:42
  SPEAKER_00: Um then there are more than 30 neurotransmitters uh in the enteric nervous system are being used by the neurons in the enteric nervous system, including, you know, those that we are familiar with, such as serotonin or dopamine or glutamate.
• 3:57
  SPEAKER_00: And in fact, so these are exactly the same signal molecules as used in the central nervous system.
• 4:02
  SPEAKER_02: Um in the brain and the spinal cord.
• 4:04
  SPEAKER_00: Sorry, in the brain and the spinal cord, yes.
• 4:06
  SPEAKER_00: Uh, which makes actually studying the enteric nervous system itself sometimes difficult, right?
• 4:10
  SPEAKER_00: Because we have such an overlapping uh they might be doing different things, right?
• 4:14
  SPEAKER_00: They might be doing different things, yes, yes, yes, yes, exactly.
• 4:17
  SPEAKER_00: Uh, which is the exciting part.
• 4:19
  SPEAKER_00: Um, and then from a communication perspective, the enteric nervous system signals and receives information from the brain via something that we call the vagus nerve, and we'll talk a lot about the vagus nerve today.
• 4:30
  SPEAKER_00: Uh, and maybe what's important and interesting in this sort of communication perspective is that um uh when you think about sort of the signaling and the receiving, it's really uh, I'd say 90% of signaling uh to the brain and only 10% of receiving.
• 4:46
  SPEAKER_02: But um, so the gut the gut is actually telling our brain stuff more than the brain is telling the gut what to do.
• 4:51
  SPEAKER_02: Yes.
• 4:51
  SPEAKER_02: This is interesting, because you made a comment earlier that it's sort of a semi-independent network in the gut, right?
• 4:58
  SPEAKER_02: It's not depending on the brain to tell it what to do.
• 5:01
  SPEAKER_00: That is correct.
• 5:02
  SPEAKER_00: The brain can influence what it does, um, and you know, especially in diseases that is relevant.
• 5:08
  SPEAKER_00: Um, but there is, you know, it has a very strong independent um signaling role, yes.
• 5:14
  SPEAKER_02: So I I don't want to spend that we there's a lot that I want to talk about, but uh just listening to this, I feel like I need a picture in my brain of some of these things we're talking about.
• 5:25
  SPEAKER_02: You're talking about how many neurons there are, and it's you know, very complex, it's got similar sort of structure, architecture, chemical makeup, cellular makeup to the brain.
• 5:34
  SPEAKER_02: How is it uh give us a picture of of what the enteric nervous system looks like?
• 5:38
  SPEAKER_02: And and also I'd love to get a picture of sort of what the vagus nerve looks like.
• 5:42
  SPEAKER_02: Because the gut is a big, long, complicated place.
• 5:45
  SPEAKER_02: And it's hard for me to imagine a nerve from the gut to the brain.
• 5:49
  SPEAKER_02: Yes.
• 5:50
  SPEAKER_02: How is that set up?
• 5:51
  SPEAKER_00: Yes, this is my favorite subject.
• 5:53
  SPEAKER_00: I love looking at uh, you know, how neurons are organized within the gut, right?
• 5:58
  SPEAKER_00: Because you you already uh mentioned, I think, one of the big challenges, which is that the gut is extremely long, right?
• 6:03
  SPEAKER_00: And we consider sort of the enteric nervous system from the sort of esophagus um to the to the anus.
• 6:10
  SPEAKER_00: And so it's a very, very, very long region.
• 6:12
  SPEAKER_00: And so uh my lab has looked a lot at the organization of the enteric neurons, and uh what turns out is is that they are organized into rings that basically embrace uh the gut tube.
• 6:28
  SPEAKER_00: So they're still localized within the wall of the gut, right?
• 6:31
  SPEAKER_00: So you have to you can imagine that if you take out the gut, the neurons are within the wall of the gut.
• 6:35
  SPEAKER_00: Uh but when you sort of would slice open the gut tube and put it into a sheet, they would look like stripes, right?
• 6:42
  SPEAKER_00: So you have the neurons, uh lots of neurons aligned into uh a stripey structure, so to say.
• 6:49
  SPEAKER_00: Um, and the stripes or this organization differs within different regions.
• 6:54
  SPEAKER_00: Like, for example, regions in the small intestine look very different than regions in the colon, which makes total sense because in the small intestine we have very different functions of these neurons than in the colon.
• 7:03
  SPEAKER_00: Um, there are uh functions such as nutrient absorption or water retention or um you know fecal matter production.
• 7:13
  SPEAKER_02: Yeah, it's a whole it's a whole assembly line in there, right?
• 7:16
  SPEAKER_02: Yes, exactly.
• 7:16
  SPEAKER_02: From gathering the nutrients to getting, you know, pulling out the water and all those things.
• 7:20
  SPEAKER_02: So it's but it's ring, it's sort of rings all the way through, but the way that those rings are organized around the gut is it varies as you go through.
• 7:28
  SPEAKER_00: Varies, yes.
• 7:29
  SPEAKER_00: Uh and there is a um there's a substructure within these rings in that uh the neurons that are sort of organized into what we call ganglia.
• 7:38
  SPEAKER_00: Um and it is these ganglia.
• 7:40
  SPEAKER_02: It's like a cluster.
• 7:41
  SPEAKER_00: Clusters, exactly, clusters.
• 7:42
  SPEAKER_00: Uh and these clusters, they form these rings.
• 7:44
  SPEAKER_00: Um and somebody, uh Laurie even Dershowitz, when she was a graduate student in my lab, uh, coined these clusters mini-brains.
• 7:51
  SPEAKER_00: So now I always think about my gut tube as lots of little mini-brains, you know, because they have these interneurons and sensory neurons and motor neurons arranged in these clusters that are arranged in these rings uh along the length of the gastrointestinal tract.
• 8:05
  SPEAKER_00: Uh and they, um, as we discussed, uh are slightly organized differently depending on where uh you are, uh depending on the function that they have to do.
• 8:14
  SPEAKER_00: But overall, right, they are working together to make sure that um you know the sort of um our process of digestion happens in a normal way.
• 8:25
  SPEAKER_00: And then you asked about the vagus input.
• 8:27
  SPEAKER_00: Right.
• 8:27
  SPEAKER_02: Are those all sort of coming out of those?
• 8:29
  SPEAKER_02: I'm imagining those like coming out of those ganglia making goes to the brain, is that wrong?
• 8:34
  SPEAKER_00: This is a um current research topic.
• 8:37
  SPEAKER_00: Um we don't know yet.
• 8:39
  SPEAKER_02: Okay.
• 8:39
  SPEAKER_00: We we don't know yet exactly, um, and it's actually it's a super interesting question of how the vagus influences the enteric nervous system, or vice versa, right?
• 8:49
  SPEAKER_00: Um is there, you know, other particular cell types that might be targeted, for example, could it be that the vagus is uh interacting with uh, you know, for example, sensory neurons in particular for the enteric nervous system?
• 9:04
  SPEAKER_00: Or is it just random?
• 9:06
  SPEAKER_02: That's so interesting.
• 9:07
  SPEAKER_02: And this this makes uh the the project that we're gonna be talking more about later in the conversation all the more important to understand that while we know that the gut is doing really important things for our digestion, and digestion is critical not only for our survival, but we've heard over and over, these are the I hear conversations all the time, about the field of neuroscience realizing how important the gut is to things we used to think of as exclusively the territory of the brain.
• 9:37
  SPEAKER_02: We've heard things on the show about, you know, constipation and Parkinson's disease.
• 9:42
  SPEAKER_02: We hear all kinds of things about gut processing and mental health, depression and anxiety and so on.
• 9:48
  SPEAKER_02: And anyone who's ever had a gut problem knows the connection with anxiety very well.
• 9:52
  SPEAKER_02: I mean, there's there's like a a very there's a very obvious connection, I think, that most people are can imagine.
• 9:58
  SPEAKER_02: So it's interesting because uh, you know, having come up in in neuroscience, this was never a topic of conversation when I was in graduate school or, you know, undergraduate or anything.
• 10:08
  SPEAKER_02: And it's it's a little surprising because we are so used to thinking about our behavior and our emotions and our cognition in a very brain-centric way until you think that like, well, we all evolved from worms and like basically we're a tube for like taking in nutrients and and getting extracting energy from our environments to do interesting things with.
• 10:32
  SPEAKER_02: So it made me think that I don't know, we talk about the gut as the second brain, but maybe we should talk about it as the first brain, right?
• 10:40
  SPEAKER_00: Yeah, so it's true, right?
• 10:41
  SPEAKER_00: Uh there is um, you know, a lot of the conferences I go to, there's there's sometimes this sort of um we we talk a lot about this.
• 10:48
  SPEAKER_00: Why not call the gut the first brain?
• 10:51
  SPEAKER_00: Um and actually what you pointed out is is interesting.
• 10:54
  SPEAKER_00: Like if you think about this from an evolutionary um perspective, right?
• 10:58
  SPEAKER_00: Sort of motorcellular um animals like ancient sponges or sea anemones or jellyfish, um, you know, they uh developed a gut uh long before uh developed anything that resembles a brain, right?
• 11:12
  SPEAKER_00: So the gut was there before.
• 11:13
  SPEAKER_00: And also when you think about sort of the the embryonic development, gastrulation occurs very, very, very early.
• 11:20
  SPEAKER_00: I think once sort of the animals involved and uh you know moved away from just drifting to uh actually uh moving forward, uh, I think then they developed sort of a uh for like a front end and the back end, and the front end, you know, sort of has all of the sensory elements like eyes and receptors that sense sort of chemical changes.
• 11:42
  SPEAKER_00: So I think evolutionary uh one could make the argument that the gut was there before before the brain, and that the brain was built around the gut or to sort of move the gut towards the food.
• 11:54
  SPEAKER_02: Um so in a way, I mean you could imagine the I mean there it makes more sense to think about ways in which the gut might be in charge.
• 12:00
  SPEAKER_00: Yes, right?
• 12:01
  SPEAKER_02: The brain the brain is there to serve the gut, not the other way around.
• 12:04
  SPEAKER_02: At least not entirely.
• 12:05
  SPEAKER_00: Yes, yes, and actually, um uh you know, I I'm a big fan of uh Julia Anderson.
• 12:10
  SPEAKER_02: I've got the book right behind me.
• 12:12
  SPEAKER_00: Oh, okay, good, good, good.
• 12:13
  SPEAKER_00: Yes, that book.
• 12:14
  SPEAKER_02: This is this great book called The Gut, which which you give to basically everybody.
• 12:18
  SPEAKER_02: I give everybody.
• 12:19
  SPEAKER_00: Yes, yes, that's right.
• 12:20
  SPEAKER_02: It's one of these books that you read and then you're like, I need to read that again.
• 12:23
  SPEAKER_00: Exactly, yes.
• 12:24
  SPEAKER_00: Um so right, so she comes back to this idea that uh, you know, as I said before, the uh most of the information or a lot of the information actually comes from the gut to the brain, right?
• 12:33
  SPEAKER_00: Um and that travels along this nerve, the vagus nerve.
• 12:36
  SPEAKER_00: And she really puts forward this this thought that uh the gut really works as a sort of as a massive sensory organ.
• 12:43
  SPEAKER_00: While, you know, we are not having conscious gut thoughts, there is a direct sort of feeding of the information that's happening in the in the gut to the brain, um, and really influences our emotions and thought processes.
• 13:01
  SPEAKER_02: Yeah, it feels like it's part of this bigger conversation about taking taking what we think of as our, I don't know, our consciousness, our cognition, our minds, whatever you want to call it.
• 13:10
  SPEAKER_02: I've been reading Michael Pollan, so forgive me if I'm you know waxing philosophical here.
• 13:15
  SPEAKER_02: Yes out of the skull and thinking of it as something that occurs throughout our bodies.
• 13:20
  SPEAKER_02: Right.
• 13:20
  SPEAKER_02: The brain is specialized for certain aspects of this, but there is a lot going on in our bodies that we that we that we really think with or feel with or are aware of our bodies.
• 13:31
  SPEAKER_02: And for maybe for most people this is like pretty intuitive, but in neuroscience it's a kind it's a bit of a new thing to say, oh, let's look outside the brain.
• 13:50
  SPEAKER_02: So let's talk about this project that you have that tries to get at some of these big questions about whether we want to call it communication between the body and the brain, how the body influences our behavior, or thinking about behavior outside of just the brain.
• 14:06
  SPEAKER_02: This is um a project that's that you're doing with several other faculty members that focuses on that most special of feelings, which is being stuck in bed with a stomach bug.
• 14:16
  SPEAKER_02: And before we get into the details of that project and and sort of how it came about, why study sickness?
• 14:22
  SPEAKER_02: Why study how sickness influences our behavior?
• 14:25
  SPEAKER_02: How does this help us think about some of these questions about the brain and the body and how they communicate?
• 14:30
  SPEAKER_00: Yeah, so um, you know, when we get sick, um, that clearly has effects on our brain.
• 14:37
  SPEAKER_00: There is uh oftentimes an inflammatory uh process that is associated with sickness.
• 14:43
  SPEAKER_00: Um, and there are inflammatory mediators or proteins or signaling sort of components that are called cytokines, that travel to the brain and really uh change our sort of behavioral priorities, maybe in uh, you know, in in in sickness.
• 15:02
  SPEAKER_02: Right.
• 15:03
  SPEAKER_02: So we know there's some kind of communication going on there.
• 15:05
  SPEAKER_02: And and you know, when you think about it, when you get really sick, it does change your behavior.
• 15:09
  SPEAKER_02: Your your project focuses in particular on this idea of fatigue.
• 15:13
  SPEAKER_02: Why is it that we just like cannot get out of bed, even if we're usually a go get it, I'm gonna go to I'm gonna go to work no matter what.
• 15:20
  SPEAKER_02: Sometimes you get sick and you're just in bed all day, and there's not much you can do about it.
• 15:24
  SPEAKER_00: And I think actually I should have emphasized that.
• 15:26
  SPEAKER_00: We we used to think about this as okay, so now we get sick, we are fatigued, we can't go to work or we can't do our normal um activities, and we want to really try to um change that.
• 15:38
  SPEAKER_00: And uh oftentimes that's you know, we take some medicine and treat the symptoms, but uh sort of the fatigue aspect of this uh it's a little bit more of a nuisance at the moment, right?
• 15:49
  SPEAKER_00: Because we can't just do what we usually do.
• 15:51
  SPEAKER_00: What what we are really um trying to do is to emphasize the fact that fatigue is in fact, and you know, I know that the field has uh changed a lot in looking at fatigue as something actually positive, right?
• 16:04
  SPEAKER_00: As something what we call an adaptive response, meaning a a change that helps us uh, for example, conserve energy.
• 16:12
  SPEAKER_00: It allows us to, for example, um redirect our power or resources towards the immune system uh to fight off the infection.
• 16:21
  SPEAKER_00: And uh in lots of ways also, you know, by us just staying at home and uh lying in bed, it sort of limits uh the sort of the spread of the infections um to the community and really accelerates uh healing.
• 16:35
  SPEAKER_02: I love that idea.
• 16:36
  SPEAKER_02: I had absolutely never thought about that before.
• 16:38
  SPEAKER_02: But the idea that that being confined to bed is a is a sort of uh quarantine that your own brain is doing as a pro-social response to prevent like you can imagine this evolving in commun in a social species like us as a way of preventing the spread of disease.
• 16:56
  SPEAKER_02: Plus, it helps you redirect energy.
• 16:58
  SPEAKER_02: But this I you have this phrase in the the sort of project proposal for for this for this um research of um fatigue as a behavioral reflex to getting sick.
• 17:11
  SPEAKER_02: And so it seems like such an interesting way of asking about communication between the body and the brain to say, okay, we've we study reflexes in the spinal cord, you know, things where you know you burn your finger and you jerk your hand away, um, you know, hit your knee and your leg moves back like they do at the doctor's office.
• 17:28
  SPEAKER_02: But this is the idea of a behavioral reflex coming through of probably other through other circuits in the body where somehow, and this is the subject of of your research, somehow there is a detection that there is an infection, there's a virus, there's something going on, and the brain responds with this pretty significant behavioral change that does not permit you to get up and walk around beyond just being a side effect of your body's using a lot of energy to fight off the disease.
• 17:56
  SPEAKER_00: Yes.
• 17:57
  SPEAKER_00: I mean, what's really interesting in this comparison is that the reflex circuit in the spinal cord is so well studied, right, that it sort of serves as the toolbox to uh look at what are the molecular mediators that are important in this reflex in the spinal cord, right?
• 18:12
  SPEAKER_00: And so that's really what we want to get to in the in our system as well, except that we are so far behind uh in knowing what the reflex itself is, right?
• 18:22
  SPEAKER_00: And so what we need to do is um really do a very sort of the defining this, I mean you could call it broof and it's a big word, but uh really mapping this reflex for the um the the sort of the gut-brain axis in the context of fatigue.
• 18:40
  SPEAKER_02: Yeah, so to trying to understand this reflex, and as you say, like we've the these spinal reflexes have been studied for ages and ages.
• 18:47
  SPEAKER_02: Now let's figure out what is this reflex that's going on when we're sick.
• 18:51
  SPEAKER_02: And so you've got a fantastic team, you uh uh as the expert in the enteric nervous system and spinal reflexes, understanding these circuits.
• 19:00
  SPEAKER_02: Luis de la Saia, who's an expert in the brain circuitry of sleep, to help us understand, well, what are the circuits in the brain that like switch on when we're sick to confine us to bed, essentially, to get this terrible feeling of fatigue.
• 19:15
  SPEAKER_02: And Christophe Theis, who is really interested in these questions of you know, the back and forth communication between the body and the brain across the vagus nerve and so on.
• 19:24
  SPEAKER_02: Um so sort of a dream team uh came together partly to at the Neuroscience Institute retreat a few years ago, where we but basically asked researchers from different parts of the university to come together and say, how could we move this field forward?
• 19:39
  SPEAKER_02: Uh I wish I could have been a fly on the wall uh at that table where you and Luis were talking about this.
• 19:45
  SPEAKER_02: Was there a particular moment?
• 19:46
  SPEAKER_02: I mean, do you remember any particular moment from that conversation where it occurred to the two of you that, you know, if we studied fatigue, we could really move this field forward.
• 19:54
  SPEAKER_02: It would answer a lot of questions, maybe beyond the specific questions we're going to study.
• 19:59
  SPEAKER_00: So, so as you said, so the the initial idea of just even working together came at the Usai retreat.
• 20:06
  SPEAKER_00: You know, at the time uh the the call for the big ideas wasn't out yet.
• 20:10
  SPEAKER_00: But Lewis and I, we found ourselves at the same table and both immediately thought about sort of you know connecting his expertise, as you said, on brain sleep with my expertise on gut function.
• 20:22
  SPEAKER_00: And then I um I had known Christoph Heis from actually a conference on the Galapagos Islands.
• 20:27
  SPEAKER_00: Um, I knew, of course, of his expertise uh in uh gut brain access on how external influences might mediate gut brain access um and challenge that, and especially on the immune system.
• 20:40
  SPEAKER_00: And I think it was just through uh Christoph joining the team that we thought about, you know, not just not just sleep, but also about the moment when, you know, it all goes away basically in fatigue.
• 21:25
  SPEAKER_02: Um I want to think through how you all are going to tackle this question of how this behavioral reflex happens.
• 21:35
  SPEAKER_02: And it seems like there are three main components there, and maybe we can talk a little bit about what we know about these things and what the real questions are that still need to be addressed.
• 21:44
  SPEAKER_02: We need to know, like, how does the body know we're sick and how does it communicate that to the brain?
• 21:50
  SPEAKER_02: What we think is going on in the brain that takes in that signal and says, Okay, we need to stay in bed.
• 21:57
  SPEAKER_02: Um, and then there's another aspect.
• 22:00
  SPEAKER_02: Of the project, which seems really interesting, which is how much how does that actually help?
• 22:05
  SPEAKER_02: Does it actually help us get better?
• 22:07
  SPEAKER_02: Or maybe it is more of a quarantine thing like we were talking about before, where it's not really about you, it's about you not getting everyone else sick.
• 22:16
  SPEAKER_02: So maybe maybe we can tackle a few of those.
• 22:18
  SPEAKER_02: First, let's start with the brain.
• 22:20
  SPEAKER_02: I, you know, I did come up in neuroscience.
• 22:22
  SPEAKER_02: I'm going to start with the brain.
• 22:23
  SPEAKER_02: There was a fascinating study that you mentioned in sort of laying out this project that I think is really instructive, um, that suggests that there's a sort of memory of illness in the brain.
• 22:37
  SPEAKER_02: Can you tell us a little bit about that study and how it influenced the way you're thinking about what you're looking for in this project?
• 22:45
  SPEAKER_02: What are you looking for in the brain?
• 22:46
  SPEAKER_00: Okay, awesome.
• 22:47
  SPEAKER_00: Yeah.
• 22:47
  SPEAKER_00: Um, yeah, so uh very beautiful study.
• 22:50
  SPEAKER_00: Um it was done by um Astra Rolls' lab, um, was uh actually a postdoc with uh Lewis, and they found that the brain basically can memorize or or trigger an immune memory in the context of of um like inflammation.
• 23:09
  SPEAKER_02: What does that mean, an immune memory?
• 23:12
  SPEAKER_00: Meaning that uh there is a particular region in the brain called the insula.
• 23:16
  SPEAKER_00: Basically, what they are suggesting or showing is that there is literally a sort of a circuit or physical blueprint of uh past sort of inflammatory events.
• 23:27
  SPEAKER_00: And very specifically, actually, because they have shown they have shown that different uh sort of inflammatory cues can trigger distinct um sort of circuit uh activation.
• 23:40
  SPEAKER_02: That's so fascinating.
• 23:40
  SPEAKER_02: So they made I think this was in mice, if I remember correctly.
• 23:43
  SPEAKER_02: That's correct.
• 23:43
  SPEAKER_00: Then yes, yes, very important.
• 23:44
  SPEAKER_00: Uh it's not in mice.
• 23:46
  SPEAKER_02: They made mice feel sick in a couple of different ways.
• 23:49
  SPEAKER_02: Yes.
• 23:49
  SPEAKER_02: And they saw representations of those in the brain.
• 23:51
  SPEAKER_02: And this is the part that kills me.
• 23:53
  SPEAKER_02: They could trigger re-trigger the body's response to those two different kinds of you know, nausea or whatever it was by stimulating the brain.
• 24:02
  SPEAKER_02: Yes.
• 24:02
  SPEAKER_02: Which suggests that the brain still has some sort of behavioral trigger that's stored in the brain and not in the body.
• 24:09
  SPEAKER_00: Yes, super cool.
• 24:10
  SPEAKER_00: Yes, I um I agree.
• 24:11
  SPEAKER_00: I think sort of thinking about uh the brain memorizing sort of the inflammatory response to me is always um fascinating.
• 24:20
  SPEAKER_02: Fascinating.
• 24:21
  SPEAKER_02: And then seeing how that connects with our, you know, the normal kinds of tiredness that we you know experience in our regular lives.
• 24:27
  SPEAKER_02: And like is it is it triggering the same circuits or different circuits?
• 24:30
  SPEAKER_02: It sounds like there are a lot of open questions there about where exactly in the what are the cells that are responsible for keeping us in bed when we're sick?
• 24:39
  SPEAKER_02: Yes.
• 24:40
  SPEAKER_02: Um okay.
• 24:41
  SPEAKER_02: And so then I I guess the other question is, and you guys had some very interesting preliminary data on this.
• 24:47
  SPEAKER_02: What are some of the signals we think that are coming from the body to the brain?
• 24:52
  SPEAKER_02: Is this a vagus nerve signaling um approach?
• 24:56
  SPEAKER_02: What do we know about that?
• 24:58
  SPEAKER_00: So it's interesting, right?
• 24:59
  SPEAKER_00: So we generally think about two potential ways, one of them being the vagus, as I mentioned, right?
• 25:04
  SPEAKER_00: This is sort of the highway that connects the periphery with the brain.
• 25:08
  SPEAKER_00: There are studies where you, for example, cut the vagus, right?
• 25:11
  SPEAKER_00: Because you know, if you have a highway, if you interrupt it, that will sort of dampen that response.
• 25:16
  SPEAKER_00: Um, and then there are also circulatory factors, which are, you know, not confined to the vagus, they are in the bloodstream, and they also have the ability to signal to the brain.
• 25:28
  SPEAKER_00: So there are these cytokines, these molecules traveling towards the brain to tell it, you know, here we have an inflammation state.
• 25:35
  SPEAKER_00: And I think this comes to this question of, you know, I think fatigue.
• 25:39
  SPEAKER_00: And I don't know whether we have really vocalized that.
• 25:42
  SPEAKER_00: Uh, in lots of ways, um, if you think about the elements of the periphery, the gut, you think about the vagus or the circulatory system and the brain, they're all elements, right?
• 25:52
  SPEAKER_00: And we we talked earlier about the fact that there is this reflex circuit that we want to um map out and its actions, in fact, um, and what are the molecules that really trigger the responses.
• 26:04
  SPEAKER_00: Um in fatigue, uh, it is one of these elements is, you know, non-functional, is stuck.
• 26:14
  SPEAKER_00: We'd love to know which exactly which cells in the vagus are the ones that uh mediate sort of the information transfer.
• 26:21
  SPEAKER_00: Could it be that there's something wrong with those?
• 26:23
  SPEAKER_00: Or if we could identify the molecules that signal from the periphery to the brain, maybe there's something wrong with those.
• 26:31
  SPEAKER_00: So, you know, sort of trying to take apart this circuit will help us sort of understand more about uh how fatigue is generated.
• 26:42
  SPEAKER_02: Right.
• 26:42
  SPEAKER_02: And you bring up a a really such an important point about, you know, this this fatigue might be an adaptive response, as you guys have been have been arguing, but it can go overboard.
• 26:52
  SPEAKER_02: And and you know, I want to talk a little bit at the end about, you know, there are many, there are these chronic fatigue syndromes where what might start as an adaptive response gets stuck on and never goes away even after the sickness resolves.
• 27:06
  SPEAKER_02: Yes.
• 27:07
  SPEAKER_02: Um I want to come back to that in just a moment.
• 27:09
  SPEAKER_02: I just wanted to ask about this last idea that you brought up in in talking about these studies that that you and Christophe and Luis are doing, which is to really understand that adaptive side of things.
• 27:20
  SPEAKER_02: And this is something that I hadn't ever heard or or thought about before.
• 27:24
  SPEAKER_02: You mentioned that fatigue maybe helps keep the gut moving even when we're sick.
• 27:30
  SPEAKER_02: Um can you tell us just a little bit about that?
• 27:32
  SPEAKER_02: What is what is the hypothesis there?
• 27:35
  SPEAKER_00: So we think about um, as we talked about, peripheral inflammation sort of re uh induces um sickness sleep, right?
• 27:42
  SPEAKER_00: And we are thinking about that strengthening the immune system and sort of reserving or restoring sort of energy levels.
• 27:50
  SPEAKER_00: Um but the question is whether sickness sleep also, and if it does, how uh does sickness sleep resolve infection in the periphery?
• 28:01
  SPEAKER_00: Because what we do know is that if we have infection in the periphery, we're gonna have an effect on uh gut function, gut motility is changed.
• 28:09
  SPEAKER_02: Interesting.
• 28:10
  SPEAKER_02: So it's how does how do these signals that you know there's an infection, we've got a virus, something like that?
• 28:17
  SPEAKER_02: Not only how are those changing behavior through interacting with brain circuits, but how are those changing the workings of the gut itself in a way that maybe the fatigue helps, or maybe it's just a separate sort of signaling pathway, other other nervous system reflexes that are triggered by being sick?
• 28:33
  SPEAKER_00: Aaron Powell Yes.
• 28:33
  SPEAKER_00: And so for example, let's say you have you're fatigued and you want to catch up with sleep.
• 28:38
  SPEAKER_00: Um if you now interrupt that catching up of the sleep, right?
• 28:41
  SPEAKER_00: If you now interrupt that process, um what's the effect uh on the on the gut, on the periphery.
• 28:50
  SPEAKER_02: You brought up a f a moment ago that one of the objectives here is to understand not only how the system works when we're healthy, but also how it goes wrong in disease.
• 29:01
  SPEAKER_02: And you know, these chronic fatigue syndromes I think they, I mean, my understanding is they they used to be, and maybe in some cases still are, often kind of dismissed by our medical system in part because well, in part because m standard medical tests couldn't really explain what was happening, right?
• 29:17
  SPEAKER_02: It looks like someone's just tired.
• 29:19
  SPEAKER_02: Are they malingering?
• 29:20
  SPEAKER_02: Are they, you know, just don't want to go to work?
• 29:22
  SPEAKER_02: Is it is it all in their head, which is my least favorite thing.
• 29:25
  SPEAKER_02: People always say that, as if that means it's not real, right?
• 29:27
  SPEAKER_02: Like so much thing, so much all of us is in our head and in our bodies, and like that's that's what we're trying to to figure out.
• 29:34
  SPEAKER_02: Um it seems like after the pandemic with long COVID, that there's been a real shift in in taking these kinds of disorders much more seriously.
• 29:43
  SPEAKER_02: Yes.
• 29:43
  SPEAKER_02: Where are you going to be looking to try to understand what is going wrong in these chronic fatigue disorders as opposed to just the regular fatigue that we experience when we have a flu or something?
• 29:57
  SPEAKER_00: Yeah, so I think you're uh what you said was is absolutely correct, right?
• 30:01
  SPEAKER_00: Um I think um sort of the non-resolving fatigue, we don't have diagnostic tools.
• 30:05
  SPEAKER_00: There's no blood test, and these diseases are sort of um defined symptomatically.
• 30:12
  SPEAKER_00: Um and so having a biomarker would be uh really fantastic.
• 30:17
  SPEAKER_00: But to get to a biomarker, we need to do basically the research that we are proposing.
• 30:23
  SPEAKER_00: We need to sort of understand again how the factors that we, for example, propose come from the periphery, um, you know, where they originate and how they get to the brain, right?
• 30:34
  SPEAKER_00: Which encompasses all of these questions of sort of the origin, the pathway, and where in the brain they might um play a role.
• 30:43
  SPEAKER_02: Aaron Powell And to the extent people have looked at this, is this idea of, well, maybe we need to look in the body, maybe we need to look at the gut and the immune system and so on as for those biomarkers.
• 30:53
  SPEAKER_02: Is that is that a new approach to this?
• 30:55
  SPEAKER_00: Yes.
• 30:56
  SPEAKER_00: Uh I would argue it's a new approach.
• 30:57
  SPEAKER_00: Um I think it is going away from sort of the brain-centric approach, really uh taking into account the entire body.
• 31:04
  SPEAKER_00: And you know, I think the benefit or the difficulty from just looking at the brain, I think it's complicated and um potentially less accessible for eventual medicine.
• 31:16
  SPEAKER_00: Um and you could potentially administer uh medicine much easier via the gut.
• 31:23
  SPEAKER_00: You know, that might help us to um sort of find biomarkers, uh treat chronic fatigue in a novel way.
• 31:31
  SPEAKER_02: Before we end, um I just wanted to return to this idea about you know how holistic thinking about the body and the brain uh can help us, I don't know, in in regular speech we say get out of our own heads, right?
• 31:44
  SPEAKER_02: Like in neuroscience, we've been very much in in the head and trying to understand the circuits of the brain, which are nice and complicated and very important, but that the brain is there to do much more than that.
• 31:54
  SPEAKER_02: Um I'm just curious if if you see there being a a shift in perspective from just being in the brain to thinking about brain-body circuits that that the field could use or that might come out of this this type of project.
• 32:10
  SPEAKER_00: Yes.
• 32:11
  SPEAKER_00: So as we alluded to at the beginning, I I as you said, I mean I think um generally the field has moved away from the sort of uh brain-centric view to a more body-brain, uh gut-brain interactive state.
• 32:26
  SPEAKER_00: And I think in this case for fatigue, um, as I said, I uh we hope that um our proposal and our research will bring opportunities uh to further understanding fatigue and it emphasizes the importance of uh sort of moving just out of the central of the brain into the periphery.
• 32:47
  SPEAKER_00: Um and we we do think that you know new biomarkers or new medical um intervention uh might be found from expanding to uh the uh body-brain circuit and understanding how it regulates sickness sleep and really understanding their physiological benefits from modifying um and understanding um the periphery.
• 33:09
  SPEAKER_02: And it just it just emphasizes again so much how you need people from different disciplines to answer questions like this.
• 33:14
  SPEAKER_02: This is not something that any one lab could do, right?
• 33:17
  SPEAKER_00: I mean it's and yes, and I would like to emphasize that.
• 33:19
  SPEAKER_00: I think it's actually super important that science um, you know, is moving towards a uh you know transdisciplinary um approach.
• 33:29
  SPEAKER_00: And it maybe it's it I mean it's already there.
• 33:31
  SPEAKER_00: And I think this this proposal is a nice illustration of how that would be uh without it, you know, without me working with Christopher and Lewis, this project wouldn't be possible.
• 33:40
  SPEAKER_00: And it's through our sort of combined expertise, which combines the brain and the gut, um, and actually somebody who works exactly on the on the element that connects us.
• 33:50
  SPEAKER_00: I think that that it's gonna be very powerful.
• 33:52
  SPEAKER_00: Um, as you said, dream team.
• 33:55
  SPEAKER_02: Well, I so look forward to seeing the results of these studies and learning more about why I feel so terrible when I um when I get when I catch a stomach bug and how maybe it's really good for me.
• 34:04
  SPEAKER_02: Um and also for all these people who who have long COVID and and these chronic fatigue syndromes, like finally getting a biomarker for that, finally having an idea of where to release that emergency break will just be so transformative.
• 34:17
  SPEAKER_02: So thank you so much, Julia, for coming on from our neurons to yours.
• 34:20
  SPEAKER_02: It's been a pleasure.
• 34:22
  SPEAKER_02: Yes, always a pleasure talking to you.
• 34:24
  SPEAKER_02: Thanks.
• 34:25
  SPEAKER_02: Thanks so much again to our guest, Julia Kultschmidt.
• 34:29
  SPEAKER_02: She's a professor of neurosurgery at Stanford Medicine and a faculty scholar here at the Woodside Neurosciences Institute.
• 34:36
  SPEAKER_02: To read more about her work and our big ideas in Neuroscience Initiative, check out the links in the show notes.
• 34:41
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• 34:47
  SPEAKER_02: We also love hearing from listeners.
• 34:49
  SPEAKER_02: If you have thoughts about the show or questions about the brain you'd like to hear us discuss in a future episode, send us an email.
• 34:56
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• 34:59
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• 35:02
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• 35:06
  SPEAKER_02: It may seem like a small thing, and I know everyone asks this, but it is tremendously valuable for us to be able to bring more listeners to the frontiers of neuroscience.
• 35:19
  SPEAKER_02: From our neurons to yours is produced by Michael Osborne at 14th Street Studios with sound design by Mark Bell.
• 35:25
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• 35:32
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• 35:34
  SPEAKER_02: I'm Nicholas Weiler.
• 35:36
  SPEAKER_02: Until next time.