Dogma-challengers. Another discovery in the thalamus
For the thalamus, you will find the name of the Acsády group. And if it is the Acsády group, you will sooner or later realize that nothing in the thalamus is as we have thought for a hundred years. A study published in Nature Neuroscience, with Nóri Hádinger as the first co-author, describes a new cortico-thalamic pathway.
Isaac Asimov, a pioneer and classic of science fiction, has created an exceptionally large and popular oeuvre. His life's work has been marked by science journalism and his articles, written in a highly readable style. Having earned not only a degree (1939) but also a doctorate (1948) in biochemistry from Columbia University, we can believe his comment that
"The most interesting phrase to hear in science before a new discovery is not "Eureka!" (I found it), but "That's strange...".
The truth of the phrase is acknowledged by many researchers, and not only because, although contemplating in a bath of warm water can be very pleasant and useful two thousand -two hundred years after Archimedes, too, for financial and environmental reasons, taking a shower is nowadays preferred.
All joking aside, it must be quite strange how many discoveries have been found to be not quite as, or quite different from, what we thought and were taught as dogma.
A prime example of this in the case of brain research is the thalamus, which for a long time we thought we knew everything about, but then it turned out we didn't. And László Acsády and his group played a major role in rewriting the history of the thalamus. The discovery and its story, published in Nature Neuroscience in December 2022, are worth reading not only because it proves Asimov's pithy quote, but also because it shows that you can't achieve outstanding success in science without persistent hard work.
Nóra Hádinger (Nóri), the first author of this article, has a lot to say about this. Let's start at the beginning!
-The story of this article started with a completely accidental discovery. I was looking at the results of a viral pathway discovery under the microscope, and after the candidate cortical fibers were where I expected them to be, I looked at the thalamic areas where they shouldn't be as a control. But there they were.
This initially made me uncertain about the reliability of the experiment. When I later ruled out possible technical errors, I began to wonder what was really going on. At first, I just examined our existing anatomical material in turn, focusing on this, then I designed a few simpler experiments until I was quite sure that this was an exciting new discovery. Finally, I convinced Laci (Acsády) that this was something interesting to work on.
- What was this discovery?
- We found a new cortico-thalamic pathway!
- Explain in a little more detail, please!
- We have discovered that cortical 5th layer pyramidal (L5) cells make synaptic connections with cells located in the thalamic reticular nucleus (TRN), the inhibitory nucleus of the thalamus.
This is of particular interest because the literature to date suggests that these L5 cells only innervate the stimulatory cells of the thalamus and do not directly affect thalamic inhibition. Our results have therefore basically rewritten the "textbook" knowledge!
This in itself would be interesting, as one would think that the basic connections between the cortex and the thalamus had been mapped out long ago. What makes the discovery really exciting, however, is that the pathway we have described is region specific, only between the frontal cortex and the associated TRN areas.
The other cortical regions (including, for example, sensory cortical regions) are not, as far as we know, connected to the TRN via the L5 output.
- Does this excellent observation and description of the pathway have other significance besides drawing attention to the fact that this region is different from the others?
- The discovery is very timely because, although we have now come to understand that the thalamus interacts closely with all cortical areas with diverse functions, we have very little information about how the connections between the two brain areas are modified according to the different modes of operation.
- Can you give us a brief overview of this?
- The primary sensory cortex receives sensory information from the thalamus predominantly from the periphery, while feedback from the cortex to the thalamus mainly modifies how the thalamus filters these stimuli according to what the cortex needs at the time.
However, the frontal cortical areas we studied do not directly receive primary sensory information. The roles of the thalamus and corticothalamic connections in the latter neural circuits must therefore necessarily be quite different. The activity characteristic of frontal cortical areas is persistent activity. This can be observed in the operation of short-term working memory, or in the preparatory processes preceding the onset of movement. These processes are characterized by dynamic changes over time, both in the cortex and in the thalamus, of the cells that determine the activity of the area. What is more, in order for this "activity program" to play out, intact corticothalamic or thalamocortical connections are required. It also follows from the above that not only the activity of the two brain areas is constantly changing over time, but also the communication between them. So this is not the general filtering function of the thalamus that we have been taught so far! The cortical and thalamic activities that give rise to/trigger each other change dynamically, moment to moment, and cell population to cell population.
- How does your discovery relate to this?
- We have shown that momentary changes in cortical activity are highly transmitted to thalamic inhibitory cells. We also demonstrated experimentally that the L5-TRN pathway is essential for the precise coordination of cortical and TRN functions.
- Why was the latter important?
- Inhibitory connections in many brain areas have been shown to play a prominent role in regulating the activity of a given area. And our findings suggest that the corticothalamic pathway possesses the properties necessary to dynamically coordinate the function of these two brain areas.
- You were the original observer, you designed and carried out the experiments that convinced Laki that it was worthwhile to continue. How did it continue?
- This project really started as a little "love project" that I started doing little by little alongside my main project, so I was then in the privileged position of being able to participate in practically the whole process from the birth of the idea to the writing of the last sentence of the article. I was very lucky that Laci supported me all the way and let me develop my ideas. Except for the in vitro electrophysiology part, I did all the experiments, in part or in whole, including experiment design, data analysis, and programming.
- All the experiments????
- Yes, but I was not alone. I also have to thank our two Ph.D. students, Emin Bősz and Bogi Tóth, who helped me with the experiments, Krisztina Faddi, who took a lot of work off my shoulders as an assistant, and our Swiss collaborators Anita Lüthi and Gil Vantomme, who did the in vitro experiments. Of course, without Laci's confidence, ideas and criticism, this publication would not have been possible, nor would it have been possible without the support of the laboratory and the KOKI.
- This is not the scientific part of the story, but it is almost as interesting. When did you start working on this topic "from scratch" and what techniques did you have to learn?
- The first, all-encompassing experiment was in May 2013, then ten years ago, but I've only been working on this full-time since 2017. Unfortunately, in the meantime, a collaboration gone wrong took away a precious year and a half, so roughly 5 years was the actual time it took to complete the experiments and the article itself.
I had used the anatomical techniques used in the article before, but the in vivo electro-physiological methods and the programming skills needed to analyze the physiological data were acquired specifically in the context of this project.
- Undoubtedly, all of these will provide valuable background for later. How inspiring is it for you to learn new tools and processes?
- It's the other way around for me. I am inspired by the question and if I need new methods to answer it, I will learn them if there is an opportunity. I think it's important that even if I don't do all the experiments, I have the knowledge. That way I know what could potentially go wrong in an experiment, I can interpret the raw data, and I can discover correlations that might have escaped my attention if I had just received the ready-made figures from someone else.
- I can totally agree with that! And I also understand how much you can take ownership of the whole piece. However, one can assume that you've had enough of it at times. It simply took too long. When was the hardest?
- Hoping to enrich the material with new behavioral biology experiments, I spent a year and a half in New York since 2016. This period proved to be very mentally taxing for me and my confidence in science was set back for a long time. I'm proud that I didn't let these experiences break me, that I managed to find my way back to the enthusiasm that got me going, and that we were able to put together a nice, rounded story without the experiments in question.
- My heartiest congratulations! Let me also ask you, what was the point, the achievement, when you knew it was going to be a really significant work?
- Basically, I approach every experiment with a naïve, childlike enthusiasm, and every time I hope that something interesting will be discovered. This time I had reason to believe that the discovery was really remarkable because it was so contrary to the textbook data that for a few days after the first experiment was evaluated I was really disappointed because I thought I had messed up the experiment, that we were seeing what we shouldn't be seeing.
- As usual, some of the results are presented at conferences. What was the feedback?
- Over the years, I've had a lot of positive feedback at conferences, but it was really at this year's Gordon conference on thalamocortical interactions that I felt this work was something that could change the way we think about the interaction of the cortex and thalamus. I now felt not only that the results presented were recognized as beautiful, thorough work, but also that researchers could relate to it through their own work. For example, in one of the post-presentation question sessions, it was mentioned that based on the BioRxiv version of the paper, one lab is already planning a new series of experiments! That was an incredible feeling!
I feel that the timing of the publication is very fortunate because the current issues in the field have now changed in such a way that our results have become really relevant.
- Were you lucky with the reviewers?
- We had three reviewers, and fortunately, all three were basically enthusiastic about the paper, but they were far from giving us "Accepted" status for free. We answered a total of 72 questions in two rounds, which together amounted to 67 pages. Out of these 72, there were a lot of formal comments, and taking them on board has definitely improved the structure of the article. Many questions were raised because space constraints forced us to omit many otherwise important details from the article. These questions were finally answered with two new additional figures, which we have now retrospectively concluded are very welcome in the final version.
The critiques did not change much in my judgment of the importance of the work, but I did learn a lot about writing an article and the way an external expert looks at our work.
- I know a discovery doesn't necessarily have to have an immediate benefit, but with more and more neurological diseases being identified and prevention-cure options still missing, I ask, does it?
- Our results provide a basis for a better understanding of the frontal cortical function and for research into neurological diseases in which both TRN and frontal cortical function are involved. These include schizophrenia, autism spectrum disorders, and attention deficit disorders, which are affecting an increasing number of people and whose origins are still not fully understood.