Sep 2020 – Anthony Sclafani & Lisa Beutler

We eat because we need, because we want: find out why

On September 8, 2020, we opened our 2020-2021 season with a virtual conversation with Dr. Lisa Beutler and Dr. Anthony Sclafani. We will be posting the podcast and recordings soon!

Dr. Beutler is an Assistant Professor of Medicine at Northwestern University Feinberg School of Medicine. She is a physician scientist aiming at how the gut and brain communicate with each other to maintain body weight. Dr. Beutler received her MD and PhD from the University of Washington, where she studied how input from NMDA receptors onto medium spiny neurons (a type of inhibitory cell in the basal ganglia) is critical for learning in Dr. Richard Palmiter’s laboratory. She then proceeded to specialize clinically in endocrinology and began studying how a subset of neurons in the hypothalamus (AgRP) neurons are involved in regulating hunger in Dr. Zachary Knight’s lab and is currently studying how obesity affects the ability of these neurons to detect certain nutrients.  

Dr. Sclafani is a Professor of Psychology at Brooklyn College at the City University of New York. He has had a truly distinguished career of over 50 years in studying the neurochemical circuits that govern learned taste preferences. He has served as the past-president of both the Society for the Study of Ingestive Behavior and the Obesity Society and has authored over 300 publications. Dr. Sclafani began his research into ingestive behavior in Dr. Pete Grossman’s laboratory where he developed a wire knife to dissect neural pathways involved in an obesity syndrome generated by damage to the hypothalamus that elicited overeating. From there he has pioneered studies that have helped to answer how specific features of food promote appetite and the brain reward systems that are activated from the consumption of palatable foods. 

Episode 14: Developing A Connection

Dr. Kaltschmidt 0:02
Okay, so it is soft. There was a tiny bit of spice. It’s egg white with some thing spicy on top like paprika pepper or something.

Peter 0:16
Yeah, perfect. That’s exactly what it was. It was some paprika on top. I was looking on your website and you do some work on sexual function. Eggs and reproduction. Eggs are things that develop, wondering you know, try and tie something into.

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 focus on the crosstalk between gut and brain. We invite speakers in this field to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the astronauts podcast.

Welcome back. Today we have Dr. Julia Kaltschmidt. Dr. Kaltschmidt is a Wu Tsai Neurosciences Institute Faculty Scholar and an Associate Professor in the Department of Neurosurgery at Stanford Medical School. She received her undergraduate degree in Molecular Biology and Biochemistry from the University of Madison, Wisconsin. She then completed her PhD at the University of Cambridge in the UK, where she trained as a developmental biologist and studied the cellular mechanisms underlying early Drosophila nervous system development in the laboratory of Dr. Andrea Brand. During her postdoc at Columbia University, she began working with mouse as a model system, and became interested in mechanisms that underlie sensory-motor circuit connectivity in the spinal cord. She continued to explore the development and molecular regulation of spinal circuitry as an assistant professor at the Sloan Kettering Institute in New York City. And during this time, the focus of her laboratory expanded to include neuronal circuits that underlie sexual function as well as gut motility. So I want you to tell us a little bit more about your research path. I’d love to hear especially some more about the transition from your PhD to your postdoctoral phases.

Dr. Kaltschmidt 2:44
Hi, Okay, first of all, thank you for having me on this podcast. I’m very excited to be here. As you mentioned, during my PhD, I worked on fly development, particularly looking at neuroblast developmen. And after my PhD, during my postdoc, I have to be very honest, I was very interested in gastrulation, and was heavily invested into looking at labs that study gastrulation. But then decided to interview broadly, and I ended up interviewing a lot of different places all in the United States, and settled on Tom Jessel’s lab at Columbia, where we studied spinal cord circuitry in mice. That, of course, is very different from gastrulation. But I was, you know, I was very much interested in these questions of neuro-circuit formation, which of course, I had a window in during my PhD. And, you know, it was I was very attracted to Columbia to the colleagues at Columbia to the city of New York. So yeah, it was a not straightforward path, via gastrulation. But just to tell you, I thought very broadly, I was not exactly knowing what I wanted at that stage.

Peter 3:57
Yeah, and in retrospect, would you have done anything different now thinking back upon the decision […]?

Dr. Kaltschmidt 4:03
That’s an interesting question. I think all the experiences that you have in life, they shape you who you are. And I think, from that perspective, I think it’s very difficult to say I would have wanted to do something different, because, you know, it sort of made me who I am. And to me, that’s very valuable.

Peter 4:21
Yeah. So could you tell us a little bit more about some of the work that you did during your PhD?

Dr. Kaltschmidt 4:26
So, during my PhD, I worked on neuroblast development, and […] I took the approach of live imaging, which I think at the time was relatively novel. And so I had a GFP marker that would visualize the spindle. And what I noticed, and I remember actually, the moment I noticed it’s that the position of the mitotic spindle rotates during this process of cell division in the neuroblast’s division. And I remember this moment because I printed out my data, it was late at night, and there was a postdoc in the lab. And I printed this out and it was all fuzzy, right? I mean, the picture was, in retrospect, not ideal. But I, I printed it out. And I showed it to him. And I remember him saying, oh my God, do you know what you what you just found? So I found that basically, prior to the division, epithelial cells divide such that the determinants that are localized on one side of the cell get divided up into both cells equally. But for neuroblast, what happens is, is that the division is perpendicular, right? such that the determinants go into only one of the daughter cells. And to mediate that right do you have to have a it’s a 90 degree change in the axes of division. And so what I found is is that the spindle gets assembled as if an epithelial cell would divide. But then during mitosis rotates 90 degrees, and then it’s a quick flip. And then the cell divides in the perpendicular orientation. And this flip was what my PhD was about.

Peter 6:22
That’s really cool. So what I guess I’m trying to visualize what are the implications of this flip? Did you mention that the components of the cell are unevenly distributed after the flip?

Dr. Kaltschmidt 6:32
Correct. So the components you know, they are imagined, I wrote a review on this. And I tried to find a good analogy and it’s a piece of cake, right. So imagine you have chocolate cake was a raspberry frosting and on top of raspberry or a cherry, whatever. And so usually you would divide a few divided right in the middle, both people get the same. However, if you would imagine cutting 90 degrees separate Then one person gets the cake and the other one gets the frosting and the cherry, right. And so that’s the same for the for the neuroblasts. So the daughter cell gets all of the components, which is different from the mother cell.

Peter 7:14
And then understanding the mechanism of why I guess or how this neuroblast divides unequally, what are the implications for this?

Dr. Kaltschmidt 7:23
Potentially? Well, yeah, so then I went on to show that there was a mutant executable, that would not complete this flip, and would divide at a at an angle. And that, of course, then means that the determinants are not any more 100% unequally distributed, but sort of somewhere in between in between, and that has a of course, a change, or an implications for the cell fate of the cells and the cell fate and the determination of I guess, the entire nervous development.

Peter 7:58
Great. So for me gastrulation is a huge process, right? All the organs are developing everything within the body is developing. I know that you focused a bit on the nervous system in particular, was there an emphasis on the spinal cord? Or was the spinal cord something new that you had gotten into?

Dr. Kaltschmidt 8:12
So the spinal cord was something new. To me, the spinal cord is really interesting because it has a direct link to motor output. So studying the circuits of an organ that you can measure its effect directly on locomotion. It’s exciting.

Peter 8:30
Yeah, for sure. And then the other thing was that you had previously done your work in Drosophila as a model system.Then you transition to the mouse. Was there a thought that was going through your head? Were you thinking about I want to work with the mouse model system from now on or tell us some of the pros and cons in your mind about working between these two model systems?

Dr. Kaltschmidt 8:47
Yeah, to be honest, that very interesting question. I was curious about the mouse. And when I started doing my post-doc work, I very quickly realized that at the time, the tools that I was familiar with in total filler could not be translated to the mouse. And that was difficult to realize, because it was basically, you know, I wanted to do X, Y, Z, and I couldn’t do it because it wasn’t, you know, very limited with tools. So I think that was definitely a realization that I had. Of course, that’s also exciting because you can generate new tools, right? So there’s a pro for that. But coming from the fly in that sort of immediate wanting to do things space, there was a setback. But the other thing which, you know, you asked me earlier on about the transition from PhD to postdoc, mice, of course, are more expensive, right? And if you think about, I took them the approach from postdoc to faculty, and I stayed in mice that, of course, is expensive, right? I did not think about that. At the time when I was choosing my postdoc, right? I didn’t think about oh, you know, this might influence my, my expenses downstream. But, you know, some people might think about that. I didn’t, but that’s good. Clearly is a big difference.

Peter Weng 10:01
So what exactly would you say the benefits of working in a mouse model system for what you’re trying to study over within the Drosophila? [The act of] gastrulation is [different] in mouse versus the Drosophila. But studying spinal cord development is very different as well.

Dr. Kaltschmidt 10:15
Right. So I think, you know, of course, the knowledge that we gain from understanding synaptic specificity in the spinal cord of mice, ideally, should be applicable to our understanding of human synaptic specificity, particularly in the realm of, you know, we’re very interested in trying to understand what the molecular underpinnings are of the particular circuits, that knowledge should be beneficial for, for example, spinal cord injury, and you know, regrowth and recurrent activity of the axons. And that actually leads a little bit to what my lab now studies. Since our move to Stanford, it has taken up a lot of studies of the gastrointestinal tract and we have a project that basically links the spinal cord with the GI tract. Because one of the co-morbidities of spinal cord injury actually is colonic dysmotility. And we have a strong interest in trying to understand the interconnectivity of the spinal cord in the gut. And, you know, how that might be disrupted or affected in spinal cord injury.

Peter 11:18
Yeah, that’s really interesting, completely different part of the body that you’re studying the neurons within. I wanted to ask a little bit more about if you could describe your lab’s vision or focus in a sentence or two, what would you say it is? Because the spinal cord is thought of as quite disparate or not really that connected with the gut until now.

Dr. Kaltschmidt 11:37
So I mean, it’s difficult to say that in one sentence.

Peter 11:41
Or as many as just a brief idea what the vision of your laboratory is.

Dr. Kaltschmidt 11:45
So the vision is historically we tried to gain a molecular understanding of synaptic specificity, particular of the inhibitory control of the sensorimotor reflex arc and the spinal cord and more recently, we have come to take the approach of applying the tools and the knowledge that we have gained in the spinal cord to try to understand some of the questions in the enteric nervous system, which is again trying to understand the circuitry of the enteric nervous system and an understanding of that. If we understand what particular cell types do, what’s the effect of manipulating these on the, for example, under pressure ulcers of the of the GI tract? And as I said, there’s this one project, which in the lab currently that connects both.

Peter 12:27
So could you give us a little bit more information for those who are not as familiar with how neurons develop specificity within synapses? How does one neuron within the brain or within the spinal cord decide to form a synapse with another neuron within the enteric nervous system? I know the process is very complex, but from a kind of 30,000 foot view, how do you view these connections?

Dr. Kaltschmidt 12:47
I do not know yet the answer to the spinal cord connection, but I can give you our insight on the sensorimotor, or the gabaergic inhibition of the sensorimotor reflex arc. We know a lot more about that. I’ll give you an example. So very briefly, just to describe the circuits, there are three important synapses, the sensory afferent terminal, which forms a contact with motor neurons. And then there is this gabaergic inhibitory neuron that forms a contact directly onto the sensory afferent terminal. And we’ve asked what these three units, we’ve asked questions about, you know, what mediates that specificity between the gabaergic neuron and the sensory afferent terminal. Why is it not forming a contact onto motor neurons. And so we found an adhesion molecule complex, some parts of those complex are expressed on the sensory afferent terminal and another one on the GABA pre terminal. And if we remove them from either one, you can see that the number of these GABA pre terminals is reduced. So in this case, it’s a sort of an adhesion molecule mediated synapse.

Peter 13:49
And are these the three components that you think are necessary and sufficient? Or do you think there are other components that perhaps may play a role in this?

Dr. Kaltschmidt 13:56
Oh, I think there are other components as well. I mean, there’s data on positional identity. Yes. So I think, right the the other question is, for example, we can have an adhesion molecule for every particular synapse, that’s different, right? So you have to think about different concentrations of different components. So there’s definitely something else that’s going on.

Peter 14:16
So within this gabaergic interneuron, is the specificity the same with all sensory nerves.

Dr. Kaltschmidt 14:25
Great question. So we do know a lot about the sensorimotor connectivity, right, because flexors and extensors have a very particular specificity. And we don’t know very much about the gabaergic specificity besides the fact as I just said that it forms contacts on sensory afferent terminals and motor neurons. And so right, is it that you have a population that acts as an umbrella and every gaba pre terminal, or do you actually have specific effects versus extensor our pre populations that might inhibit one versus the other? And that’s exactly what one of the projects we’re doing in the lab. I’m very excited about this one. That’s exciting. I can’t wait to see you. Thanks for asking that question.

Peter 15:03
No problem. The other thing I’m wondering is whether or not this complex that you’ve seen, because we gabaergic inter neurons throughout our nervous system, have you seen this complex anywhere else outside the spinal cord? And or have you looked in other locations?

Dr. Kaltschmidt 15:17
So we haven’t looked, but it is in other systems in the brain, which makes it of course more applicable.

Peter 15:24
For sure. And then I guess the other thing that goes through my mind, as I think of this relatively naively is before you can even form this connection, you have to get there’s neurotrophic molecules, do you have a good understanding of what the factors that are being secreted that bring these guys together?

Dr. Kaltschmidt 15:39
So again, great question. No, and you’re right. So if you think about the process of synaptic specificity, there is, you know, you can take this, take it apart into different units. And one of the questions is how does the cell know which target regional lamina to go to right, and then once it reaches there, whether it can distinguish In different cell types, for example. The lamina specificity, or the in this case, the regional specificity, which is close to the motor neuron cell bodies, we do not know what mediates that. We would love to know that it’s a process that happens in the first postnatal week. We know that. And we do know that if you remove this, if via genetic surgey get rid of the sensory endings close to the motor neurons, these gabaergic neurons will Project ventually into the spinal cord, but then we retract so they will not form a contact on anything else that is not sensory terminal. So they will not seek out an ultimate target such as the one on or on or another synapse.

Peter 16:40
So there’s, in a sense, this act of constant communication, right? Because if there’s the sensory cell that’s not there, maybe it’s not receiving that signal. The beginning of time, this neuron or this interneuron isn’t really feeling motivated. I guess if we want to anthropomorphize.

Dr. Kaltschmidt 16:53
Yeah, right. Yeah. See, we call this process a stringent specificity, right? Because it’s not it’s not seeking out an ultimate synaptic finding partner, but the point being that it still grows eventually, right? Is something that is not coming from the sensory open terminal, because that’s not there, that attracts the neuron to go there. And the question is what that is?

Peter 17:14
So presumably, there’s two different molecules, right one that is involved in bringing it over, and the other one that gives it that specificity or more, but at least

Dr. Kaltschmidt 17:21
People can think about two steps in that process, at least.

Peter 17:24
Yeah. And is that stringent specificity? I guess? I am always wondering about generalizability of synaptic specificity, and I wondered whether that stringent specificity has been shown in other areas of the nervous system,

Dr. Kaltschmidt 17:36
Not to my knowledge. So in the opposite of stringent specificity, which you could call hierarchical specificity is shown in the fly, right. So you can think of the motor neurons innervating muscles, and also in C. elegans, I would say they are examples of hierarchical specificity. So it’s a no, not yet.

Peter 17:59
I think that makes it interesting. As to why this came about, right? I want to segue a bit more to another aspect of your job. We talked briefly about the gut, but there was another aspect on sexual function. Yeah. What drew you towards understanding sexual function: from sexually specific sensory information? Yeah, and the spinal cord connections there.

Dr. Kaltschmidt 18:18
Yeah, you know, I, it is a my lab website listed as an equal important project. We have, at the moment, no active research in the sexual circuitry, but we did. And we actually see the sexual circuit as an alternate circuit to locomotion. It innervates differently in the spinal court. And so we were using it as a sort of the yin-yang of trying to see how a different functional circuit, right, very different function, how that synaptic specificity is guided or correlated with different function.

Peter 18:56
Okay, can you walk me through a bit about the circuit I guess I’m not that familiar with the parts of it and all the moving components.

Dr. Kaltschmidt 19:03
Right. So all we did basically is we injected into penile muscles. And okay, so the injection is a Cholera toxin subunit B, which is our traditional injection, which we have injected before into a hind limb muscles. What that does is it labels the motor neurons as well as the set of sensory afferent terminals. And so that’s our way of labeling where cell bodies aren’t where the projections are. So yeah, basically what we did is we injected into a couple of penile muscles and what we notice is that the sensory afferent projections do not reach the locomotor muscles directly to the motor neurons. They’re basically innervating the dorsal spinal cord. And we basically use that as a space for comparison. Because the proprioceptive the locomotor, the muscle innovated in you know, we simplified by saying, well, it forms contact on the motor neuron, but it of course also has a dorsal branch. And that is in very close relationship to the penile muscle, sensory branch. And so we had something that was close vicinity and comparable.

Peter 20:04
So in your view, correct me if I’m saying this incorrectly, you’re using this other, I guess, motor system to study synaptic specificity, and it’s, in a way a different validation or a way to see whether a different mechanism of synaptic specificity is being involved. And then we touched upon the gut aspect of it. And you told me that this is something that you’re very interested in. Could you tell me about some of the work that has been done to show this connection between the two?

Dr. Kaltschmidt 20:32
So as I said, we are we are new to the field of the gut. This came about, and I did elaborate on the fact that it just came about because of spinal cord injury, right. It actually came through one of the seminars in the neurosurgery department. I learned that there was this really strong sort of comorbidity of gut dysmotility. And so we look closer and there is not a great understanding of what the connectivity is between the colon and the spinal cord. Is there one, right? I mean, there’s clearly a textbook suggestion that there is connectivity via, you know, sensory neurons going from the colon to the spinal cord and via post ganglionic neurons going to the gut. But we primarily, we were interested in a mapping the sensory integration. And so we basically injected CTB, into the colon to see what we see, that has revealed quite some interesting connectivity aspects.

Peter Weng 21:27
Yeah, that’s interesting, because I think one of the things that our laboratory really talks about is this connection is this drive to find food, right, this patient, it would be interesting in my mind to see whether a) the architecture is there that’s present and then b) can we modulate this architecture?

Dr. Kaltschmidt 21:43
Yes. And if it was, the way I think about this is that, you know, is there an architecture that’s there that we can use to, to drive peristalsis via the spinal cord.

Peter 21:58
And then the other thing that comes to my mind is you were mentioning this comorbidity associated with people who have spinal cord injury and colonic dysmotility. Yeah. I wonder whether or not people who have colonic dysmotility are more susceptible to developing spine injuries?

Dr. Kaltschmidt 22:15
I don’t know whether it is. But I think about it that way around. I mean, think about it the other way around, right? Because you’ve interrupted the spinal circuit, because there isn’t interconnectivity. We are disrupting somehow the motor function. And you’re right, there are other, you know, besides spinal injury, there is Parkinson’s disease, there’s autism, all of those have gi dysmotility phenotypes. Right. And the question is why? I think it has a lot to do with actually the enteric neurons themselves. One question in a lab is whether, you know, autism associated genes are expressed in the enteric nervous system.

Peter 22:52
I think that’s reasonable. It’s just, I guess my thought is whether or not this pathway has the potential to be bidirectional.

Dr. Kaltschmidt 22:58
I see what you mean. Yeah. Possibly

Peter 23:01
It’s an exciting avenue. I feel like there’s a lot out there for us to figure out. And then the other thing that comes to mind is, is there a way to tie together the synaptic specificity between these different motor circuits like the erectile dysfunction with this gut dysmotility? Or is there like any way to tie all these circuits together?

Dr. Kaltschmidt 23:18
Yeah, so that I don’t know. But, you know, actually, if you look at spinal cord injury comorbidities that are listed by patients as wanting to be corrected, or suffering most it is first colonic dysmotility, then its sexual function and then its limb function. So sexual function is clearly also affected. I do not know to what extent there is a link, right. But both circuits could be going through the spinal cord, right.

Peter Weng 23:48
I think intuitively, it makes sense that they are going but understanding I guess, the specificity of how these circuits map. Yeah, very interesting.

I want to ask a bit more about some of your writing actually. So I noticed that you had recently published a preview in neuron titled, chandelier cells swipe right for l1cam. I thought the title was very interesting, right? I, I think it really draws the attention of people who are in kind of modern day society looking at their apps and swiping left or right Why do you think the titles for previews and news and views are so different from the titles in actual articles?

Dr. Kaltschmidt 24:44
Interesting. So first of all, I need to credit my postdoc, Ryan Hamnett for that title. He’s the first author of this preview. And it’s a spectacular writer. Each time I write a preview. I think I am I feel challenged to Come up with a title that is sort of fun and has a second meaning that makes people think. I think it’s there are no real restrictions to that. I personally think that a title for a paper should be very precise. I think every word in that title shouldn’t be visualized in the paper. So right. So when I read the title, I would love to see that reflected in the paper. It’s almost like a mini summary. Why that is? Maybe traditionally so right? I mean, maybe because it doesn’t allow for overstatements.

Peter 25:42
And then I guess what you just mentioned made me think of these graphical abstract abstracts that certain journals have. What do you think the value of a graphical abstract is if your title should give you that image?

Dr. Kaltschmidt 25:53
Well, you know, okay, I personally love graphical abstract. I do spend a lot of time making graphical abstracts. I once taught a class where I also that was one of the assignments doing a graphical abstract. You’re right. That might seem a double effort to summarize the paper. However, I think it has different values. Right? I’m personally a very visual person. So I look at this graphical abstract, and I really get a lot of information out of that. So I think it is perfectly valuable to have both, you know, the the graphic abstract, I think can include more, more content, maybe more detail.

Peter 26:28
Right. So one of the principles that you had mentioned for your title is that it should give you a very precise specific image of what is to come in the paper. Yeah, with regards to creating an image that summarizes your entire paper, are there any principles that you focus on or follow?

Dr. Kaltschmidt 26:43
I’m a very visual person, I was actually accepted to art school originally, and so I had to make this decision between art and science. And I think it has influenced how I make figures for a paper and how I you know, I we have our confocal in the lab and love imaging. So it’s very important to me. And when I think about a graphical abstract, I think trying to make it in a sort of minimalistic style, which still represents the message I think is essential. I’ve done graphical abstracts and I, you know, generally I have too much stuff in my graphical abstract at first and then I think the challenges is to make it clear to sort of minimalize, to sort of conceptualize, I think that’s a challenge. I think it’s not easy to make it graphical abstracts that are actually good. But I think it’s actually um, it’s good also for the person who makes it because it’s, you really have to think about the most, most important things in your your paper.

Peter 27:45
Interesting. One other question that I wanted to ask is, I saw that you are a co-editor in chief for the journal Neural Development. Can you tell us a bit more about this position and why you chose to pursue it?

Dr. Kaltschmidt 27:55
You’re right. So I’m co-editor in chief of rural development lots of reasons why I think this is an important position. First, I want to say, I have really amazing co-editors. It’s wonderful to work as a team. And so if you look at my research, we do molecular neurobiology. If you look at the history of molecular neurobiology, I think, I think it’s an important field that is very important to be continued. And of course, you know, we have functional data added and very valuable additional information. Neural development is a very, I’d say, traditional journal, which focuses on neural development. As such, it is very important to me that it continues to get the attention as a research field. When I was invited to be co-editor, I said yes, because I think it is an interesting challenge nowadays to keep that research field on the on the radar of all minds.

Peter 28:57
You had mentioned molecular neuroscience as being a classic field, I think of at least in my neurobiology courses discrete between molecular neuroscience and systems neuroscience gotten very popular, right? Why do you think molecular neuroscience is important for neural development?

Dr. Kaltschmidt 29:13
I want to make clear that, you know, I think all the other fields are very important to right. But at the end, if we understand how something functions, we understand the systems biology. At the end, I think it is very important to know how these connections are made, right? It’s to me, it is important to know, you know, what are the molecules or the mechanisms or the the rules that make particular synapses personally, to me, that is sort of the the essence of synaptic circuits: how does it interconnect? And so it’s, rather than looking at a bigger entity or building it’s, it’s trying to look at, you know, how does the brick fit in the wall Next to the other brick.

Peter 30:02
Yeah, certainly, I think what I, what I’m hearing is you really like to zoom in to see, there’s this huge system that’s going on. We can only study it if we study it piece by piece and what you’re interested in, is that really the glue that holds the bricks together.

Dr. Kaltschmidt 30:17
Yeah. And it’s, you know, it’s, um, it’s a difficult word than glue, actually, because glue, oftentimes to me means it doesn’t mean specificity. Right. So you have to imagine a glue that only glues certain parts.

Peter 30:30
Yeah, it’s like a lock and key maybe more specific.

Dr. Kaltschmidt 30:33
Exactly what it is right. It’s a lock and key.

Peter 30:35
Yeah, you’re right. Think that’s the classic.

Dr. Kaltschmidt 30:37
Yes, absolutely. Yeah.

Peter 30:38
Really neat. Well, I want to thank you so much for your insights and your time.

Dr. Kaltschmidt 30:43
Yes, it was fun. Thank you.

Peter 30:54
Dr. Kalschmidt walked us through some of her scientific work on what are the molecules, mechanisms and rules that allow neurons to make connections. And along the way, we learned about how she thought about working with a particular model organism and the importance of being precise with our language, and especially in our titles.

With that, I want to thank you all so much for listening and we’ll see you on the next episode.
For more of our content, you can follow us on twitter @gutbrains or visit our website @thinkgastronauts.com.The Gastronauts podcast would be impossible without our incredible team. Meredith Schmehl is our producer and theme music composer. And special thanks to the founders of Gastraonuts: Dr. Diego Bohórquez and the Bohorquez laboratory.

Episode 13: Curb Your Consumption

Dr. Kanoski 0:00
Definitely fruit. I believe it was an orange and a blueberry, if I had to guess.

Peter 0:10
Yeah, you can open up your eyes. Perfect. It was a bit of a fruit salad. Some of it had fallen out but you got the tangerine and the blueberry exactly what it was the reason why these fruits were chosen, I was looking into some studies to see the effects of certain types of food on cognitive decline. And there have been studies that have shown that strawberry and spinach can be effective as a long term dietary intervention.

Dr. Kanoski 0:33
I actually have an orange tree in my yard in Los Angeles. We have apples oranges all the time, your own oranges.

Peter 0:52
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 focus on the crosstalk between gut and brain. We invite speakers in this field to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the astronauts podcast.

Today we have Dr. Scott Kanoski, an associate professor in the Department of Biological Sciences at the University of Southern California. Dr. Kanoski completed his PhD in Psychology at Purdue University in Dr. Davidson’s lab, his postdoctoral fellowship at the University of Pennsylvania and Dr. Grill’s lab and was recruited for a faculty position at the University of Southern California. His research focuses on neural systems that control feeding behavior. And in particular, Dr. Kanoski is interested in studying how dietary and metabolic factors can contribute to cognitive decline, as well as how environmental cues can play a role in controlling feeding.

Could you tell us how you got into studying how consumptions of sugars and fats can be linked with memory deficits?

Dr. Kanoski 2:25
Sure, this was actually part of my dissertation work when I was at Purdue University. There were a few papers coming out at that time showing links between consuming unhealthy diets, so what we would consider to be a quote, Western diet, that’s high in saturated fatty acids and sugar, with cognitive impairments. And what I wanted to do at that time was trying to understand the specific nature of those cognitive impairments that were associated with consuming these unhealthy diets that many of us- I’m guilty of times- myself consume. And it turns out that the hippocampus is a canary in the coal mine in the sense that it’s very sensitive to dietary and metabolic perturbations. So you see, even after consuming these diets for a very short period of time, you see deficits and hippocampal-dependent memory tasks. And this is referring to things like remembering what we did yesterday, or remembering how to get to work. These are memory processes that rely on this brain structure. And more recently in my lab, we’ve been trying to isolate the specific dietary factors that are causing this because a Western diet is different from a healthy diet and in many ways, and we’ve found a role for sugar independent of elevated fat content. However, the effects of sugar on hippocampal dependent memory deficits appear to be exacerbated during early life periods of development, so this is referring to the the juvenile and adolescent phase. So if you consume excess sugar during these periods, at least in rodent models, we see long lasting deficits into adulthood.

Peter 3:59
There was a lot of information there. I want to unpack here a little bit. The first thing I was wondering was how did you stumble on the hippocampus? I know the brain is a very complex region, when you looked at a dietary intervention or a Western diet, did you look at the whole brain and you looked at particular regions that lit up that showed you to focus on the hippocampus? Or did you know-

Dr. Kanoski 4:20
We actually follow the behavior. So psychology is my background. And I tend to start with the behavior and then break it down and get into the brain after that. And what we saw was impairments in memory tasks when animals would consume these diets that were similar to what you would see if you lesion the hippocampus, so starting from the behavior, we noticed a pattern. And then after that, you can look into the brain and try to understand what’s changing in the hippocampus that may be causing these deficits? Yeah.

Peter 4:47
Okay, so behavior was the main focus, and then you went to the brain regions? Interesting. And then the other thing that you had mentioned was that perhaps the brain is particularly vulnerable to these diets at a period in adolescence. Could you tell us some more about how you got into that research or how you identified that?

Dr. Kanoski 5:00
Yeah, we started this project because we thought it was important with regards to human health because if you look at who’s consuming the most sugar, at least in the United States, the highest sugar consumers are children, so they can consume up to 15 to 20% of their entire calories can come from sugar in younger populations. As we get older, we tend to consume a bit less sugar. That was one of the reasons we were interested in studying this developmental period. Just looking at what ages humans are actually consuming sugar in excess.

Peter 5:36
Do you feel that just because we consume more at this adolescent period? If we consumed more at a later period in life, would we see the same effects or is it just because the brain is so susceptible during that period?

Dr. Kanoski 5:49
Yeah, I take caution and extending our Roden data directly to humans. But in rodents, if sugars consumed in excess during adulthood, we don’t see the same pattern of memory deficits.

Peter 6:00
Interesting, well, I guess I’m past that point in my life. So, there’s no hope for me now.
And the other thing that you mentioned was your first interest in the hippocampus started in your graduate studies, your research has really stayed focused on the impact of diet on memory, from your work as a graduate student, to your postdoc to your work as a PI now. How have you been able to navigate the field of academia so that you’re able to distinguish your work that you’re doing now from the work that you’ve done previously.

Dr. Kanoski 6:30
One of the things that we look at that I think is unique in the hippocampus world is, in addition to looking at how the brain is influenced by dietary factors, we also try to understand how the hippocampus controls feeding behavior. And this is a brain region that’s not traditionally linked with the control of feeding behavior. But it is the case that our memory function influences our eating behavior. So we have to remember where we found the food what we consumed, and these memory processes powerfully influencing what we eat, and our overall energy regulation. So that’s one of the things that I think we’re somewhat unique in studying [which] is trying to link memory processes to the control of food intake and bodyweight regulation.

Peter 7:11
I can definitely see how when we were more of a scavenging or a hunter-gatherer society, it’s important to have this memory of where we got the food. And this context will help us define where we’re going to get food easily. Now that food is so ubiquitous, and our rates of obesity are so high, where do you see this kind of translating?

Dr. Kanoski 7:29
Yeah, that’s a good point. So we we don’t have to try really hard to find food now. But what the hippocampus is important for is detecting and interpreting internal cues, not just for navigating the external world. For example, if you lesion the hippocampus in rats, they’re not able to use different levels of food restriction as discriminative cues for some kind of event. It could be a foot shock or a food pellet. And then if you look at humans that have damage to the hippocampus, they also seem to be insensitive to hunger and satiety cues. So if dietary factors lead to hippocampal dysfunction in humans, this may lead to overeating potentially. If individuals are less sensitive to hunger and satiety cues, the default behavioral strategy is generally to eat more and not less.

Peter 8:18
You mentioned these internal cues. Could you give us some example of what specific internal cues? And you said the hippocampus leverages both the external and internal cues. Do we have an idea of how this turns into behavior how this is integrated?

Dr. Kanoski 8:31
We think the neurons in the hippocampus are receiving information about the external world, and then also about the internal world as it relates to hunger and satiety. And then it’s taking these different categories of information and interpreting them to appropriately guide behavior.

Peter 8:49
And are there specific molecules or hormones or mediators of these effects?

Dr. Kanoski 8:53
There are the hippocampus is sensitive and receiving information to a lot of feeding relevant systems. These are hormones, for example, that are secreted during feeding or immediately prior to feeding. Many of these signals act directly in the hippocampus. We think that some of these endocrine signals coming from the periphery from the gastrointestinal tract are in part how this internal information about hunger and satiety is communicated to the hippocampus.

Peter 9:22
Interesting. Could you walk us through, in your head, the process of what happens when we’re thinking about eating, or when we’re consuming food and how- I know this is a huge concept- but how do you think about when we’re going about eating? What factors are involved in signaling to the brain and from the gut as well?

Dr. Kanoski 9:40
We tend to eat based on fixed patterns. Most of us we don’t generally graze throughout the day until we’re full. So the meal is a very important component of how much intake we generally consume. And you can manipulate how much people consume by doing blatant manipulations like having a larger portion size, people tend to eat more. So a lot of our meal regulation is controlled by external factors; we eat three times a day, for example, we eat what’s on the plate. But what’s important is the decisions in terms of what we eat, I think is a very important determinant of how much people consume.

Peter 10:19
So could you tell us a little bit more about what you mean by that? So what we eat is a determinant of what we consume in the sense that if this is a high Western diet or a high carb, high fat diet, will that influence us to consume more to consume less? How exactly does that go?

Dr. Kanoski 10:35
Generally, foods that are unhealthy and are designed to be very palatable. So if you have a donut, for example, most people like donuts, this is high in both fat and sugar and sort of a prototypical element of a Western diet. And when something is more palatable, we’re able to consume more of it. And you get a blunted satiation response because of that positive reward experience of consuming something palatable.

Peter 11:03
Something that’s palatable actually blunts the satiation?

Dr. Kanoski 11:08
That is true. And if that’s been shown biologically in animal models, if they’re maintained on a Western diet, you see impaired signaling that’s called satiation, where we have these biological signals that arise from the GI tract during a meal, whose function is to terminate the meal eventually, we need to stop eating right. And what you see in animals that are maintained on a Western diet is these biological signals are blunted, they’re weaker, they’re less effective in terminating a meal, these satiation signals.

Peter 11:39
And where are these satiation signals coming from?

Dr. Kanoski 11:41
There’s different different signals: mechanical distention of the stomach is one. So just the physical expansion of the stomach by the food that we’ve consumed. There’s also intestinal hormone signals. One of the classic signals his cholecystokinin or cck, which is secreted from the intestines during eating. This signal acts in part to try to increase satiation and terminate feeding. And both of the two I just described, their effectiveness is blunted in animals that are maintained on an unhealthy yet palatable diet.

Peter 12:16
Interesting, we just came to my mind is sometimes our lab will bring leftovers from dinner or something and put them in our lab meeting room. And there’s it’s oftentimes unhealthy food. And it’s just because it’s there. I don’t really consider the unhealthy nature of it, but I just go about and start eating it regardless. And I was wondering, how does this play into the fact that we have these strict three time a day meals, but like, we also do this grazing when we just present we kind of impulsively just eat at it. How do you correspond these two thoughts together?

Dr. Kanoski 12:49
I’m interested in both, so I studied how the brain controls normal feeding behavior, meal frequency meal size, but you mentioned impulsivity and that’s something that that my lab is very much interested in. In fact, we just had a publication come out a few months ago on a neural circuit. So how the brain is causing individuals to be impulsive, and in this case it was impulsive, responding for palatable, rewarding foods as you just described.

Peter 13:18
And can you unpack the circuit a bit more is it part of the hippocampus is a different part of the brain?

Dr. Kanoski 13:21
It is part of the circuit. So the circuit that we identified, it originates with a neuropeptide. It’s called melanin concentrating hormone. And it’s produced in the hypothalamus, the lateral hypothalamus. And this neuropeptide communicates throughout the brain but one of the strong targets of these neurons that produce the peptide is the hippocampus, the ventral region. And what we found which was interesting if you manipulate this MCH to hippocampus pathway, the animals were more impulsive for food, but it didn’t increase their free feeding behavior. It didn’t increase appetite didn’t increase their motivation to work for the food. It was very selective to that impulsive response.

Peter 14:03
And how exactly do you determine impulsive behavior in a rodent system?

Dr. Kanoski 14:08
That’s a good question. There’s a couple ways you can do that. One is a task where the animals learn to press the lever for a palatable food, donut hole, if you will, for equivalents. And they have to learn to refrain from pressing again for a 20 second period to get the next pellet. And then ideally, the animal would press every 20 seconds and get a pellet every 20 seconds. But what animals do is they can’t wait 20 seconds, they might hit it at say 15 seconds into that period, and that’s resetting the 20 second clock. So if the animal hit the lever every 15 seconds, they wouldn’t get any food at all. That’s one of the ways the other way is a more classic task is called delay discounting. And the human equivalent, you’ve probably seen videos where you have a kid, a toddler, a small child, who’s given a marshmallow and told you can eat that marshmallow now or if you wait for. Five minutes when I come back, I’ll give you two marshmallows. There’s a task that’s comparable to that in rodents, where they, they have two levers to choose from. One gives them a small but immediate reinforcement. And the other one gives them a larger reinforcement, but after different delay periods, and it’s always advantageous to take the large reinforcement lever, but what animals do is as that delay increases, they go for that short immediate reinforcement. So these are two different impulsivity tasks. One is an impulsive response. The first one the second is an impulsive choice. And we found that this mth brain system is increasing impulsivity for both of those tasks.

Peter 15:42
Forgive my naiveness, I’m not a behavioral scientist, but I was wondering what came to mind here was addiction in some sense. So it seems like if I’m wrote in presses more frequently for a pellet, could it also be addicting and what exactly is the distinction between addiction and impulsivity?

Dr. Kanoski 16:01
Yeah, I try to avoid that term. There’s a lot of controversy with regards to whether food certain foods can be addicting. I try to stay out of that controversy. But it is the case that there are common brain circuits that are involved with both food reward, and with drugs of abuse, cocaine, heroin, for example. So they are tapping into similar circuitry, but via widely different mechanisms. I’m not one that would promote the idea that food itself is addicting.

Peter 16:28
Okay. Good to know. I was also wondering, with this idea of this melanin concentrating hormone being sent from the hypothalamus to the hippocampus. Is it in the sense that these levels are upregulated or increased during impulsive behaviors? Or are they decreased? Or is there a way to change the gain on this?

Dr. Kanoski 16:49
Yeah, that’s a good question. And we had some really surprising results. So we found via different mechanisms, if we drive up the system, the animals are more impulsive. So if we wanted to drive down system, you would predict? What would you predict?

Peter 17:03
They would be less impulsive.

Dr. Kanoski 17:04
That’s what we thought too. But that’s not what we found. We drove down the system via multiple means. And every time we did that the animals were again more impulsive. So we think of it as there’s a healthy tone of the system that keeps impulsivity in check. And if you perturb that tone in either direction, you get a release on that check on impulsivity.

Peter 17:27
What pops to my mind is, is there a way to decrease impulsive behavior, but that is very complicated now that you think that there’s this physiologic setpoint. So whenever it goes up, right to try and turn it down.

Dr. Kanoski 17:37
Or it could be an impulsive, individual that that tone is too high or too low in that potentially it could be corrected with pharmacological approaches, but it’s not. We’re not there yet.

Peter 17:48
Yeah, well, I can’t wait to see what you guys do in the near future. I wanted to transition a bit more to some of your career paths. W hen someone is becoming a new PI or someone who’s making that transition from a senior postdoc to a PhD position, what advice would you give to someone who’s just starting a laboratory?

Dr. Kanoski 18:05
Good question. For me, that was seven years ago, almost to the day. I started at USC in January of 2013. And it’s a very overwhelming thing to start a lab. But you have to just take it one day at a time. And one of my initial strategies was to not put all of my eggs in one basket, but rather have two or three different very different research projects. When I started the lab, my rationale was, NIH funding is hard to predict, right? And you may have a project that at one point was something that NIH would generally fund, but the winds blow in different directions with the funding agencies. So if you put all of your effort into one project, you’re at a risk of not getting that project funded. So what I did was try to start three different, somewhat overlapping but very different projects early on, and they’ve all slowly developed into funded projects, fortunately.

Peter 19:02
And how do you know what the magic number of projects is? If you can envision yourself doing- is three, is the magic number five?

Dr. Kanoski 19:12
I have probably five right now, you know, some people work better with more than that fewer than that. I think it’s it’s unique to each individual.

Peter 19:17
Do you think it’s also dependent on the starting size of your lab? Do you have the physical human power to go about that?

Dr. Kanoski 19:23
Yeah. And that’s going to be reflective of your your startup package, how much funding you’re given how much space you’re given when you start the lab. Another thing that I get asked about a lot is how do you hire people? Do you hire someone for a certain skill? Or do you hire someone based on a personality? It’s really difficult to describe, and we all make mistakes in that arena. But I generally try to hire people that aren’t necessarily bringing in a skill but that I find are really engaged in the research that we’re doing. I call it the fire in the belly. So if rotation student doing technically everything right in the lab, but I don’t see that enthusiasm for the research or not bringing papers to my office and excited about it, then I don’t think that’s generally a good fit for me.

Peter 20:13
And do you think your hiring practices have changed? I guess what I’m thinking is the first person that you hire often is a very big decision point for you. And do you think your thoughts on what is valuable for personnel in your laboratory has changed from this first hire to now?

Dr. Kanoski 20:27
I do, because at that point, I was just it was just me, right. And I needed to order stuff and set things up. And now I have a much larger lab. So it does change as the lab changes.

Peter 20:41
One thing that you touched upon earlier was NIH funding is really hard to predict. And you have been incredibly successful. You’ve had three aro ones recently funded and congratulations on that. I was wondering, do you have any advice [for] younger investigators trying to get this grant funding is there a particular avenue that they should approach or there’s what goes through your head when you’re trying to give someone advice for-

Dr. Kanoski 21:05
Tricks of the trade for grant writing? Certainly. Yeah. One thing that is always helped me is to focus a lot on the specific aims page. Because if you lose the reviewers there, that’s it, you’re done. So I consider that page, it has to be a masterpiece. It has to tell a story be somewhat redundant, but not too redundant. has to really connect with the reader. So I spend probably a solid month on that one page before I write the rest of the grant. And I don’t move on until that’s at least from my perspective, as close to perfect as I can get it.

Peter 21:39
Yeah. So really hone in on that specific games.

Dr. Kanoski 21:40
I think it’s critically important. Yeah. And another thing for, particularly for younger investigators trying to get fellowships, and I think we all know this, but it’s worth pointing out to get a funded template that’s close to your area of research. And you get this by reaching out to colleagues and sometimes you have that within the lab that you’re in, but it’s useful to have some kind [of] recently funded template, this is a grant for that same mechanism you’re trying to get that was successfully funded.

Peter 22:10
But then at the same time you have to differentiate-

Dr. Kanoski 22:21
Of course. It’s not that you’re using that research, but it just it’s to get you the feel of what a successful grant for that funding mechanism looks like.

Peter 22:17
That’s really great advice.

Dr. Kanoski 22:18
And you’ll find that people are generally collegial, and will share that with you.

Peter 22:23
Yeah, with this whole talk of grants, where we’re thinking where the research is going, where do you see your lab going? Or where do you envision the five projects that you’re working on? Do you see any way to consolidate them? Or do you see them as five separate projects moving into the future? I know, we’ve probably touched upon two or three of them.

Dr. Kanoski 22:40
They’re all connected in some way most of our projects focus on on some elements of hippocampus, not all of them. But to be honest, I don’t look too far ahead. I try to focus on the data. That’s what drives me. I try not to look too far beyond the data. I mean, you have to to some extent to write a grant, you have to imagine some experiments that you might do. But the nice thing about the NIH model is that it’s not a contract. You don’t have to do those experiments, you have to do something that’s somewhat related. But it allows you to follow your data, make discoveries, find unexpected results, and then go in a different direction based on those results.

Peter 22:21
Really neat. One of the other things that I think about is oftentimes we look at research and we feel it’s very removed from our day to day practice. A lot of the work that you’re doing is something that is fundamental to our day to day practice. Eating is something that we do every day and understanding what motivates our decision to go after food or when to eat is something that I think about on a daily basis. And I was wondering how your research has impacted your day to day life or are your thoughts on eating?

Dr. Kanoski 23:46
Well, I’m a vegan, and it’s probably related to what I study, but I do tend to think carefully about what I eat probably more so than people that aren’t energy balance researchers per se and it’s not unique to me, you know, a lot of my colleagues are foodies. And are chefs.

Peter 24:08
Do you mind me asking what went behind the decision for you to become a vegan? Or have you always been a vegan?

Dr. Kanoski 24:13
I’ve been a vegetarian for about 20 years and just thought I would try a strict vegan diet a couple years ago. And it’s not for everyone, but it worked pretty well for me, so stuck with it so far.

Peter 24:24
And have you looked at the effects of a vegan diet on the hippocampus? Or is there any research that you could call to?

Dr. Kanoski 24:32
Well, the problem with that is rodent diets aren’t vegan. So the baseline isn’t [there]. But it’s not something I’m interested in studying directly.

Peter 24:40
And then the other thing you mentioned was you associate with people who are foodies, not intentionally, but just by nature of the trade. And I was wondering, does your lab do food outings or do you go as a lab to go try out different types of food is food a big part of your lifestyle as well?

Dr. Kanoski 24:57
Not necessarily. I mean, personally, it is. But as a lab we do outings together, we have activities, but they’re generally not focused on food. For example, we went ziplining on Catalina Island. Recently, we’ve done a few escape rooms. We’re going to go drive ATV vehicles at Lake Arrowhead. So we do that kind of thing. But we do have a Christmas lunch at the same Thai restaurant every year. Yeah, that’s our only food activity.

Peter 25:26
Sometimes the public perception of scientists is that of people who are in white coats doing research all the time, in my kind of experience has been very different, right? We have all these lab outings, we have these activities that allow us to bond and I was wondering what do you think the value of these lab outings is for team cohesiveness or even your science in general?

Dr. Kanoski 25:49
I think the lab is version of a family. So I don’t think it’s healthy if the only way that people are interacting is in the trenches of the lab. And I try to keep things light in my lab and and not just to always talk about the data.

Peter 26:21
You mentioned earlier that someone has to have kind of a fire in the belly for you to want them to really be a part of your laboratory. What else are you looking for in graduate students? And what do you hope to instill in these graduate students as you are a mentor to them across their training?

Dr. Kanoski 26:39
I want them to enjoy the science. I think it’s important, for example, to one to plug your own data, right? I don’t want to have to tell someone, you’re falling behind. I need to see this. If someone’s really enthusiastic about the research. I don’t have to nag them about anything.

Peter 26:56
So kind of this inner drive or this inner motivation, and how do you go about instilling that in your trainees? Or is it something that someone just naturally has?

Dr. Kanoski 27:05
Yeah, I mean, I don’t know if there’s an exact recipe for how you instill that enthusiasm. I think some of its inherent, but some of it comes through seeing your project succeed, or finding an unexpected but exciting result that led you in a different direction.

Peter 27:20
Have you had any of those experiences yourself that have led you to pursue a field that’s different than what you thought you were going to go into?

Dr. Kanoski 27:27
Yeah, I guess you could say that I joined Terry Davidson’s lab at Purdue, not because I was interested in feeding behavior, but rather I was interested in the hippocampus and what types of memory processes that brain region is regulating. But at that time, there were a lot of feeding related researchers at Purdue, including some that studied the gut brain axis, the vagus nerve and their thought was really influencing my thought at the time and we started to think about how the hippocampus and memory processes influence feeding behavior because at the end of the day, that’s a very important behavior for for organisms. How do you acquire food? What are you consuming? Yeah, certainly. So I got into feeding by by accident, it wasn’t my intention.

Peter 28:11
That’s nice. Just follow the research, follow the data, what you’d mentioned earlier. And you’ve talked about the vagus a bit. This is one of the projects we hadn’t talked about earlier. Could you tell us a little bit more about this vagus project that you’re talking about potentially linking the hippocampus into vagus in the gut?

Dr. Kanoski 28:26
Yeah, so the vagus nerve is 10th cranial nerve, and it’s a conduit of neural communication between the gut and the brain. So this nerve has cell bodies located outside of the brain, the nodose ganglion, and the sensory fibers of this nerve innervate, the gastrointestinal tract, other organs as well, but we’re focused in my lab on the GI tract. And one of the signals that’s carried by this nerve is something I referred to earlier, the satiation process, which leads to the termination of feeding. And that’s really the classic way that
this nerve has been studied in the context of feeding is the communication of these satiation signals. But there’s also a connection between gut derived signals the vagus nerve and the hippocampus. And we knew that before we got into this project based on some functional neuroimaging results, where if you expand the stomach, for example, you see a high level of neural activity in hippocampus. In humans, there was a study that stimulated the gastric branch of the vagus nerve. And somewhat surprising to the investigators at that time this was in 2006, was that the activity the blood flow activity, using fMRI was the highest in the hippocampus of anywhere else in the brain. So there’s this mysterious connection, but the function of that connection had not been studied in depth. And this is a project where we found that if you selectively eliminate the guts sensory nerve that innervates the upper gut, so the stomach and the intestines, you see severe impairments in memory processes that rely on the hippocampus. And we’re really interested if there’s a functional connection there. And what we then did is to try to map the pathway through which these gut signals are eventually getting to the hippocampus. And when I say map the pathway, we’re looking at what endocrine signals might be involved, what neurotransmitters might be involved, and what are the connections in the brain through which this information is getting there.

Peter 30:25
That’s really neat. Do we know like what the exact pathway is? And does it go through the hypothalamus and other regions that you had talked about earlier and whether or not this is associated with impulsive eating? Is the Vegas associated with impulsive eating as well?

Dr. Kanoski 30:38
I don’t know any links between the vagus and impulsivity off the top of my head, but we do know a bit about the pathway. But it doesn’t seem to go through the hypothalamus. In this case, there’s a connection we identified through the medial septum, which is interesting because this region connects to the hippocampus and this is one of the regions that’s most affected by Alzheimer’s disease, this colon urge acceptable input to hippocampus. And in fact, Alzheimer’s medications largely target cholinergic septal input and so we’ve identified a pathway from the gut through the medial septum to the hippocampus that we’re now studying.

Peter 31:18
That’ll be really interesting [to see] whether or not an ingestible can be derived or some pharmaceutical that targets that gut specifically to maybe perhaps lower risk of Alzheimer’s.

Dr. Kanoski 31:29
Yeah, we’re actually studying that now. Very early in the project, but we’re interested in if you amplify the gut vagus signal in models of Alzheimer’s in rodents, can we attenuate some of the cognitive deficits? That’s something we’re slowly starting to get into now.

Peter 31:46
Yeah, that’s really exciting. I can’t wait to see what you guys find out from that. Well, great. Thank you so much for your time.

Dr. Kanoski 31:51
Thanks.

Peter 32:03
Dr. Kanoski taught us how the hippocampus, an area of the brain that is traditionally thought to govern learning and memory, can control feeding behavior and energy regulation, reminding us that seemingly separate areas of our body are perhaps more closely linked than we think and may work together to regulate our behavior. Similarly, when starting up a laboratory, it is key to pursue parallel avenues of research that may seem unrelated initially but may tie together in time. With that, I want to thank you all so much for listening and we’ll see you on the next episode.

For more of our content, you can follow us on twitter @gutbrains or visit our website @thinkgastronauts.com.The Gastronauts podcast would be impossible without our incredible team. Meredith Schmehl is our producer and theme music composer. And special thanks to the founders of Gastraonuts: Dr. Diego Bohórquez and the Bohorquez laboratory.

Mar 2020 – Julia Kaltschmidt

Dr. Kaltschmidt is a Wu Tsai Neurosciences Institute Faculty Scholar and an Associate Professor in the Department of Neurosurgery at Stanford Medical School. Originally from Germany, she received her undergraduate degree in Molecular Biology and Biochemistry from the University of Madison, Wisconsin. She then completed her PhD at the University of Cambridge in the UK, where she trained as a developmental biologist and studied the cellular mechanisms underlying early Drosophila nervous system development. During her postdoc at Columbia University, she began working with mouse as a model system, and became interested in mechanisms that underlie sensory-motor circuit connectivity in the spinal cord. She continued to explore the development and molecular regulation of spinal circuity as an Assistant Professor at the Sloan Kettering Institute in New York City. During this time, the focus of her laboratory further expanded to include neuronal circuits that underlie sexual function and gut motility.

Her lab’s goal is to understand the molecular basis of neuronal circuit formation. They are particularly interested in circuits that underlie locomotion, sexual function and gut motility.

See more of her work here.

Feb 2020 – Marcelo Dietrich

Dr. Dietrich is an Assistant Professor of Comparative Medicine and Neuroscience at Yale University. His research program focuses on the molecular and cellular mechanisms that play a role in behavior and how these processes are regulated by energy metabolism. It is their working assumption that energy and fuel availability (through hunger) are key regulators of biological functions from molecular to systemic levels. Focusing on mouse models, his lab applies a variety of genetic tools to manipulate cell function in combination with electrophysiological, morphological and behavioral analyzes. It is his goal to build a multidisciplinary approach to integrative physiology, from identification of cell specific mechanisms to the exploration of how these pathways are related to whole body physiology and behavior.

He shared his recent work on neonatal development of ingestion.

See more of his work here.

JOIN US: FEB 4, 2020 @ 4PM in MSRB3 1125

The Gastronauts Podcast Season 2

Season 2 Transcripts

Episode 14: Developing A Connection (Julia Kaltschmidt, Stanford)

Dr. Kaltschmidt tells us how neurons in the spinal cord form connections with other nerves.

Episode 13: Curb Your Consumption (Scott Kanoski, USC)

Dr. Kanoski tells us how the hippocampus is involved in feeding behavior.

Episode 12: Mind The Microbes (Carlotta Ronda, Columbia; Martina Sgritta, Baylor)

Dr. Ronda tells us about how she thinks about modifying microbial communities in our gut. Dr. Sgritta tells us about how a particular bacteria can be used to treat autism spectrum disorder.

Episode 11: Jumpstart Your Career (Natale Sciolino, NIEHS & Sofia Axelrod, Rockefeller)

Dr. Sciolino tells us about how a region in your brain thought to regulate stress also governs eating. Dr. Axelrod tells us about how circadian rhythms work to govern our lives.

Episode 10: Food For Thought (Gary Schwartz, Einstein)

Dr. Schwartz tells us about how he thinks about researching how our body makes sense of food.

Episode 9: Beyond The Hypothesis (Hans Clevers, Utrecht)

Dr. Clevers shares both his research experiences and how he thinks about the scientific process.

Episode 8: Translating Disease Models (James Bayrer, UCSF)

Dr. Bayrer shares his work on intestinal organoids and irritable bowel syndrome and how we can optimize time management.

Episode 7: Developing Our Creativity (Gary Wu, UPenn)

Dr. Wu shares his experiences as both a physician and scientist and how we can develop the skills to think creatively and communicate effectively.


November 2019: Gary Schwartz

Gary J. Schwartz, Ph.D., is a professor of medicine, neuroscience, and psychiatry at the Albert Einstein College of Medicine. His lab studies how the gut and the brain interact with each other to regulate food intake and associated metabolic processes.  Their research focuses on the sensory neural controls of energy homeostasis in health and disease. They have identified the type of food stimuli that activate vagal and splanchnic sensory fibers supplying the gut, and have revealed the extent to which these stimuli influence gut-brain communication.

Their most recent efforts involve the analysis of gut-brain communication in the control of energy homeostasis in mouse models of obesity and diabetes.We have identified neurons in the periphery, brainstem and hypothalamus that integrate food-elicited signals with peptide signals that have profound effects food intake and metabolism. Data from these studies reveal that central hypothalamic and brainstem neuropeptides affect food intake and body weight by modulating the neural potency of food stimulated signals from the mouth and gut. This novel, synthetic conceptual framework is critical because it links forebrain hypothalamic structures, long known to be involved in the control of energy balance, to the sensory and motor systems in the brainstem that control ingestion, digestion, and metabolic processing of food. Future studies will use genetic mouse models of obesity and diabetes with targeted conditional neuropeptide/ receptor knockdown or replacement to determine how central neuropeptide signaling affects the neural processing of metabolic sensory signals critical to energy homeostasis.

See some of his work here.

October 2019 – Jim Bayrer

Dr. James Bayrer is an Assistant Professor of Pediatrics at the University of California, San Francisco. As a practicing pediatric gastroenterologist and physician scientist, his work focuses on the mechanisms underlying diseases like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). IBD is a multisystem problem, sitting at the intersection of the immune system, the microbiome, and the intestinal epithelium—he has focused his career on studying the latter. During his early work, he studied Liver Receptor Homolog-1 (LRH-1), a nuclear hormone receptor. He found that LRH-1 is critical for GI development and epithelial renewal. His team discovered that LRH-1 knockout in mice induces intestinal inflammation due to increased apoptosis and decreased Notch signaling. Using mouse and human organoids, he found this is a conversed mechanism. He further showed that overexpression of LRH-1 is protective against harsh chemotherapeutics and inflammatory molecules. To further investigate the role of the intestinal epithelium in health and disease, he collaborated with Dr. Nick Bellono on a landmark paper establishing that enterochromaffin cells form functional synapses with sensory nerve fibers, and that enterochromaffin cell activation triggers visceral mechanical hypersensitivity— a feature of IBS. Interestingly, in looking again at LRH-1, he found LRH-1 knockout mice have disrupted enteroendocrine and enterochromaffin cell development. In fact, his preliminary data show LRH-1 knockout mice demonstrate visceral hyposensitivity despite no change in mechanical compliance or GI transit time. By continuing to investigate this and other molecular pathways, he aims to discover targets to improve the clinical syndromes of IBD and IBS.  

See his lab’s webpage here.