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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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?
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
Yeah, you’re right. Think that’s the classic.
Dr. Kaltschmidt 30:37
Yes, absolutely. Yeah.
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.
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.