Itching to discover what the neurokinin-1 receptor neurons are doing in the spinal cord
Published! is a series of chats with women in science highlighting their publications as leading authors. If you have recently published a scientific manuscript and would like to chat with me, you can get in touch via Twitter @laurenpoppi or email <lauren.poppi@rutgers.edu>.
First, I just wanted to say a big congratulations on your publication!
I’m always interested to hear about the backstories behind papers. Were there some unexpected or cool initial findings that led to the development of this project?
The project initially started because I had written an NIH NRSA application focused on the neurons that express the neurokinin-1 receptor (NK1R) in the spinal cord, the same neurons that are the focus of this paper. That proposal was focused on the possible contributions of these NK1R neurons to the spinal processing of cold input. NK1R has been widely implicated in pain processing and drugs that block NK1R have been tested in clinical trials as pain relievers, with little success. We initially focused on testing if NK1R spinal neurons were important for cold sensitivity under normal conditions, with the idea that they might contribute to cold sensitivity under pathological conditions, like neuropathies. So, I started off thinking, “OK - I’m going to activate these neurons and I’m going to be able to drive cold sensitivity. Then I will figure out where they fit into spinal circuits”.
I used chemogenetics to artificially activate NK1R spinal neurons, but it didn’t affect cold sensation at all! At the same time I was also screening other sensory modalities, to see, “when I activate the NK1R neurons, can I potentiate responses to heat, touch, tactile, or itch stimuli?”. The only somatosensory behavior that I found a difference in when I activated the NK1R spinal neurons was an itch -- there was an increase in itch behavior when I turned on NK1R spinal neurons and then injected itch-causing substances into the skin. At that point, it got interesting. I think the real turning point was when I was preparing for a departmental seminar here at Pitt. I thought, “How am I going to tell this story of NK1R neurons and itch?” Right around the same time, several clinical studies were coming out that evaluated antagonists for NK1R as a therapeutic intervention for chronic itch conditions, and they showed a lot of promise. That became my hook -- I was going to figure out how NK1R spinal neurons influence itch, and where they fit into what we already know about spinal itch transmission. So we focused on itch, which maybe was inevitable being a part of the Ross lab, but not intentional!!
That’s really cool. So, you looked at a bunch of sensory modalities and it just happened that itch was the one that came out.
Yeah!
Were there any unexpected bumps along the way that were kind of difficult to overcome?
In my experience every project has a number of dead ends. I had wanted to do experiments that complemented the studies where I chemogenetically* activated the NK1R spinal neurons, where I would chemogenetically inhibit them instead, with the goal of showing bidirectional modulation of itch by NK1R spinal neurons. I tried that experiment, but it didn’t work. I didn’t know whether I didn’t see an effect because my tools weren’t effective enough (maybe I wasn’t silencing enough NK1R spinal neurons) or if inhibiting spinal neurons just didn’t block itch! So instead, I took a pharmacological approach to answer a similar question and found that yes, blocking NK1R on spinal neurons reduces itch behavior. One other thing I was very excited about for the project was using an NK1R antagonist that was in clinical development for chronic itch. I had made contacts with the company who was developing an antagonist and they were on board with giving me some of the drug to use in my experiments. But they stopped developing the drug unfortunately.
* Chemogenetics refers to a technique whereby a specially engineered receptor that only responds to a specific chemical is transgenically expressed in a cell population of interest, also known as DREADDS (Designer Receptors Exclusively Activated by Designer Drugs).
Oh no!
I know! But it was still interesting to have the opportunity to talk with a pharmaceutical company.
How was the writing up process?
It was good, I tend to really enjoy the writing process! Writing coincided with the COVID shutdown in March. At that time, I started finishing all of the data analysis and writing up the paper. I think had the pandemic shutdown not happened, I would have added a couple more experiments. But with the shut down, we decided to submit the story as is. When I was writing the paper my advisor Sarah and I had a target journal in mind. But when I sent it out to other lab mates to read it and give me feedback, two of them were like “Oh come on!! You have to submit this one tier higher!” It was really their feedback that made me think, “What the heck, what’s the worst thing that can happen if I shoot for one tier higher? I’ll get a desk rejection?” I’d rather have tried and be shot down than to have not tried. That was a really positive experience for me, and I really appreciated them saying “Just go for it!”
And then the paper was accepted in the journal they suggested?
Yeah! And it was pretty smooth too. I would have kicked myself if I had just settled!
That’s so cool. It’s great to have mates who will give you that extra push.
What were the major findings of your paper, and what are the next big questions to answer?
One of the main findings actually isn’t that new. NK1R is commonly described as a selective marker for spinal neurons that project to the brain. My paper shows that the majority of NK1R spinal neurons are actually locally projecting interneurons in the spinal cord, rather than projection neurons. Andrew Todd’s group at the University of Glasgow had put this idea forward probably 20 years ago. Nevertheless, the field continued to use NK1R as a selective marker for spinal projection neurons, which is problematic when making conclusions about where NK1R neurons are positioned in spinal circuits. One of the goals of my paper was to just say it louder for the people in the back! “Please stop using NK1R as a selective marker for spinal projection neurons!” I wanted to reiterate that for the field and hopefully it will be taken to heart now.
Dovetailing off of that, I also show that NK1R is expressed along with gastrin-releasing peptide receptor-expressing spinal neurons, which are thought to act as a 'gate' for spinal cord itch transmission. So, if NK1R cells are mostly interneurons they are probably also ideally located to modulate spinal itch transmission. We show some manipulations that suggest this is true.
There is still a lot that is not known about how these NK1R neurons are wired with other neurons in the spinal cord. That could be done with electrophysiology, but that’s above my pay grade (laughs). Beyond that, because NK1R has a pretty long standing role in the spinal processing of pain, an important question is whether the same or different subsets of spinal cord neurons that express NK1R are important for pain vs. itch. Getting after this question of ‘sensory coding’ is a general theme that I am interested in. The last major findings, which was sort of a cherry on top of the study, was that we were able to observe NK1R mRNA within the spinal cord of humans.
Wow, yeah. That’s awesome.
I first had access to human tissues in graduate school. I became interested in testing whether the targets I was studying in mouse models are possibly translationally relevant in humans by testing if they are expressed in the right neurons, because you might not have the same protein in the same spot of the nervous system in humans. The human spinal cord studies were really exciting for me since there really hasn’t been a lot done yet in terms characterizing different human spinal cord neuron populations. There have been a lot of RNASeq studies identifying unique populations of neurons in the mouse spinal cord dorsal horn, and it’s interesting to start to see if these hold up across species.
Definitely. You’ve made me think about my own project, I mean, “Is the protein I’m studying in the same neuronal population in humans?” I need to check! That was a super cool aspect of the paper.
I have a random question related to itch that you may know the answer to. My friend asked me just last week after she had burned herself in the kitchen, “Why, when your skin is healing, is it really itchy?”. I said to her… well… I am going to be talking to an itch expert next week so I’ll ask! (laughs)
I know a little bit about this because I was doing a lot of reading on neuroimmune interactions for a project last summer! There are itch fibers that innervate the outermost layer of your skin, and during the wound healing process, your immune system is really revved up and immune cells can release a bunch of different signalling molecules, like cytokines. In particular, a recent paper implicated a cytokine called interleukin-31 (IL-31) as being a source of wound healing itch. IL-31 can activate sensory neurons directly and it activates the subset of sensory neurons that are thought to be important for itch, but IL-31 was probably a target in the study because it has also been implicated in dry skin itch or eczema.
That’s so interesting, because when I think about inflammation around an injury, I think about how that’s protective in a way because it stops you from moving the site, or bumping it into things, to prevent further injuring yourself. So, it seems counterintuitive to have an injury generate itch because you probably don’t want to be scratching dermatitis or a burn or a wound…?
I don’t know why that is the case, but now I want to find out!
I always ask people this because I think it’s so interesting that everyone has a unique answer. What first got you interested in being a scientist?
As a kid, I was interested in science, and in middle school I was part of the advanced science program, but I surprisingly did not like it! As part of that program we had to participate in the district science fair. I remember the first year I went all in on a project that tested which type of UV bulbs were the best for growing indoor plants. I thought, “OK, well, if I have to do this I’m going to do it really well!”. I think I found the science fair pretty nerve-racking, and the second year was totally different. I wasn’t enjoying the program because I was pulled out from the main class that my friends were in. I thought, “I am going to put the least effort in possible because I just really don’t enjoy the science fair experience”. I think that’s as rebellious as I got as a kid… not trying super hard in the science fair (laughs). But now my life is basically a science fair and I love it.
In terms of how I actually got into wet lab research… As an undergrad freshman, I was looking for a job. I was trying to find something science-related, and I found a lab assistant position on the university online job postings. I was pretty interested in biology but was almost certain that I didn’t want to be a medical doctor. I went into that interview for the lab assistant position thinking that I would be helping set up for lab courses. I didn’t know what a research lab was. I thought I would be helping set up beakers or something (laughs). I show up to the interview, and it’s an actual research lab -- a Drosophila lab headed by Ed Blumenthal -- who became my mentor for the next four years. During that interview, he said “This is a trial run, and if you do well during the first year you can go on to do research yourself as a sophomore”. So I made fly food for a year, labelled vials, washed dishes, and started going to the lab meetings to get a sense of the different language they seemed to be speaking. I really took to it and enjoyed my time in the lab. I participated in a couple of summer research programs and when I was nearing graduation, applying to graduate school seemed like the natural progression. It was very surprising to me that you could get paid to get a higher degree. That was very appealing, and I just went straight into grad school.
Cool. That sounds very similar to my path.
It was kind of funny, I’m first-gen college and so are a lot of my childhood friends. I was telling them that I was going to grad school and that I was getting a stipend, they were like, “Oh you are so amazing! What an accomplishment”, and I was like, “No guys. Everyone gets the stipend” (laughs). So many interesting opportunities were not on my radar until later on in undergrad.
Do you have a fun science fact that you would like to share with us?
I have two! One is itch related and one is something I heard on a podcast. For itch, I think the social contagion of itch is a really interesting phenomenon. If you see someone scratching or even talking about itch…
Yeah, I feel itchy right now! (laughs)
(laughs) You start scratching! I went to the World Congress on Itch in 2019, which was multiple days of people talking about their itch research. I cannot tell you how much I was fidgeting during all of those talks. It’s an interesting phenomenon and speaks to how protective scratching is as a behavior. For instance, if someone in your community is scratching it might mean that they have a parasite, which could suggest that you too have a parasite - so you should scratch to get things off your skin. I thought that was pretty neat!
And the other fun fact, this is totally random, and maybe you already know this because you’re Australian. I was listening to a Science Vs podcast, and I learned that some mammals like platypuses have fur that is fluorescent under UV light.
Oh! I did not know that!
It’s a recent discovery! The podcast explained that a lab in Wisconsin was trying to find lichen in the woods using a UV light, and they happened to see a flying squirrel fluorescing bright pink. For some reason that wasn’t entirely clear to me, they also thought that platypuses might also have this type of fur. I don’t think they know why that happens or what it is for, but it seemed pretty wild. Platypuses are cyan under UV light!
That is crazy! That means that the fur is absorbing energy on some level and emitting photons so it must be for a reason. I have never seen a platypus in the wild, only at the zoo. They are really hard to spot!
You can read more about the glowing platypuses here!
You have done a bunch of science writing (or SciComm) on top of your hectic research schedule! You have written for RELIEF (which is a publication by the International Association for the Study of Pain), the Pain Research Forum, and Neuronline. Just wondering what the motivation is there for you, what you get out of communicating your knowledge and ideas?
I kind of fell into SciComm. The final paper that came out of my PhD work was published in eNeuro and Neuronline invited me to write a lay summary of that piece that was geared towards college undergrads with biology majors. It was a fun experience, but it was also shocking to me how hard it was to explain my own research in accessible terms… which seemed like a problem. That same year I heard about the Pain Research Forum (PRF) Correspondents Program and applied. That was my first formal training in SciComm and it gave me approaches to open up the language of my work so more people can access it. I really liked it, and at that point I thought, “I’m going to keep working at this”. It is really rewarding, and a nice opportunity to amplify research and also the voice of the researchers that might not be getting the attention that I feel should be getting noticed. For instance, I often highlight itch research on the PRF website, because pain and itch go hand in hand!
Throughout my SciComm experiences I have also found that I really like sitting down with people and talking about their work. It’s nice to have an intimate conversation with someone and ask them, “What do you think about this new finding, what are you excited about in your own research?”… it is just a really simple and meaningful way to connect with someone that might not happen at fast-moving in-person conferences. My SciComm writing recently led to an opportunity to moderate a podcast along with Becky Seal here at Pitt, was a really neat experience.
So many people, maybe especially this year, are tuning into podcasts more.
You can check out this podcast, the Pain Beat, here.
I was wondering, because as scientists we are often asked to write textbook chapters and articles, to do interviews and outreach, usually on a volunteer basis. We get a lot of satisfaction out of doing that because we love talking about science, but I think that people in similar positions who are experts in their fields would be compensated for that skill and ability, and for their time. I feel that sometimes scientists are doing charity work in that way. I was wondering if you thought the same and if you think there should be more PAID communications opportunities for scientists?
I definitely agree. I see many instances where scientists say, “Yes I will do this, and offer my time for free, because I care about it”. My writing for PRF is actually a paid opportunity now that I have gone through the training program. That experience has opened my eyes about being compensated for doing extra work. Communicating science to the media can be like a game of telephone. Whenever the findings of a new study are in the media, they are at risk of being misrepresented, for better or for worse. I think, who better to communicate those ideas than the scientists themselves who are making the discoveries? But we should be paid to do it! As far as paid opportunities go, I will plug MassiveSci, which offers a science communication training program. After you complete their training program you can be paid to write news coverage pieces. It’s probably something I would have pursued had I not participated in the PRF program. It would be great if there were more of these kinds of opportunities.
As you say, it’s not something that scientists can just do. It’s not natural for many of us to describe our work in a way that a non-scientist can understand. It’s something that we have to be trained to do.
It’s really hard! I’ve done a handful of SciComm articles now. I always go through a draft of an article several times to get rid of the jargon, but my editor will still catch a couple of places where I rely on jargon. It’s very challenging as a scientist to use colloquial language to accurately convey complex ideas. It’s something I’m constantly working on.
I really like your website! It makes it really easy to find your publications, your educational history, and links to all your SciComm, all on one page.
Thank you! It was my fun project when the pandemic started -- I wanted to put all of my professional interests in one place.
I think everybody should do that!
See Tayler’s webpage here.
I have found that working as a scientist can be both really fun and highly stressful. Pretty early on, I needed to develop some ways to manage that stress in order to be able to function as a good team member/human and to look after my mental health.
I happen to know that you are an avid runner!!
Do science and running go together for you, do they complement each other, and would you recommend we get out for a run today?
I love running, a lot. Running has been a part of my life for a really long time and I definitely identify as a runner. The importance of running to me was recently highlighted because last fall I had a couple of big injuries and I couldn’t run for a couple of months. I was so stressed from work and the pandemic. It really highlighted that I need running as an outlet and a source of stress management.
In terms of running and science going hand in hand… I consider myself a fairly competitive runner. Once a year, I will go through a training cycle that is ten weeks long and I end the training cycle by racing a half marathon. Because science is a really slow process - where it can take years to finish a project and reach the end goal of publication - I like to use races as more frequent end goals because they are something that I can work towards and attain in a much shorter period of time. I like writing SciComm pieces for that reason as well. I think everyone should have a hobby and use that time however they want. Sometimes when I’m running, I zone out and think about really random things. Other times, I’ll troubleshoot a problem I’m having in the lab or think about what experiment I should really be doing. But I often can’t work through a sticking point unless I let myself chill out. The answer appears when I have shut my brain off for a little bit!
So running helps you with problem solving?
It definitely helps with problem solving. Either by letting me stew on the problem or forget the problem for a little bit. Both of those things are important for problem solving! (laughs)
Stewing and forgetting! Got it! (laughs)
Finally, something that we are always talking about in the GWIS community... What does it mean to you to identify as a woman in science, and how do you hope to see that scientific landscape evolve within your career time and beyond?
At a personal level, I'm the first woman (and person) in my family to choose a career in STEMM, and navigating academia has definitely been challenging at times. But recently, some of my younger cousins have started expressing interest in STEMM careers too. I hope that because I went off the beaten path that they can also feel confident in pursuing their own interests.
Thinking more specifically about academia, there are various challenges about being a woman in academia that can be frustrating. One big thing for me is imposter syndrome. Everyone experiences imposter syndrome at some point. It’s something that I’m working on, for instance feeling like I can accept the recognition that I get. Recognition like this interview!
One thing that has been really helpful for me in battling imposter syndrome as postdoc is that the lab I’m in is mostly women. And not only are there a lot of women in my lab, but in the Pittsburgh Center for Pain Research there are a lot of other postdocs who are women. So I am surrounded by very strong, inspiring women scientists. On top of that, my PI is a woman. It’s been really nice to have a huge support network in that way, and it makes climbing the academic ladder seem a lot more doable with so many role models around. My experiences aren’t the norm for everyone, but I would like them to be.
In terms of where I would like things to go in the future, the ideal end goal would be for academia to be more diverse in all regards. I’m glad that platforms like Twitter are allowing women and others who are underrepresented in STEMM to have a platform to share their experiences and various struggles that they are encountering in academia in a candid way. Twitter offers a new way to get those experiences out to a larger audience, and I think we are experiencing a shift in attention toward these issues of inequalities and it seems like conferences (at least the ones that I have attended) now have more programming dedicated to discussions on being a woman in academia. They are working to increase diversity on scientific panels and to put an end to the ‘manels’ that have been the standard for so long. But there is still a big gap that needs to be filled. For instance, when I’m interviewing experts in the field for SciComm articles, I try to speak with both men and women so there is a balance of voices in those articles. I often find myself coming up with the same handful of women who are considered a senior expert in the somatosensory field. That is really frustrating for me and I’d like to see that change.
Do you have anything else you would like to add?
First, thank you! I appreciate how much time can go into these interviews and getting it into a nice, polished product, and it’s fun to be in the other seat! I also owe a big thank you to my mentors who continue to help me get to where I want to go.
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