The brain stem also helps you remember
While most people interested in brain research know about the role of the hippocampus in learning and memory, probably none of them know about the important role of the brain stem, considered evolutionarily ancient, in storing negative memories. But so did most researchers, until recently, when Gábor Nyiri's group published a paper in the journal Plos Biology.
Although the importance of lifelong learning has been mentioned so many times that everyone is tired of it, it's so true that it's part of the activity of a healthy brain. If you are a researcher, this is, of course, particularly true. In the case of Dr. Krisztián Zichó, it is also quite obvious that he was aware of the importance of learning even before he was a university student. After all, you cannot get a degree with a summa cum laude degree from a university that is much easier than a medical school, especially not without studying, and he managed to do so at Semmelweis University. But not only that. At our institute, as an undergraduate student in the group of Dr. Gábor Nyiri, Krisztián became one of the first authors of a paper accepted by Science, one of the most prestigious scientific journals, in 2019. As has been mathematically proven, one success leads to another. Krisztián's scholarships and prestigious awards are to be envied, but it is much better to follow his example, as the path is open to others. Our Institute welcomes applications from enthusiastic, hard-working, and talented students and university students like him!
We are now talking about another major discovery, an article published in Plos Biology. Let's start with what has happened since 2019.
- In 2020, I received my medical degree from Semmelweis University and since then I've been working as a PhD student. I can say that a new world has opened up for me, as time is no longer limited. I have been able to become more and more immersed in scientific work, from expanding my knowledge of the literature to brainstorming and carrying out experiments. All the members of my group and my supervisor helped me with this, for which I am grateful. The first major result of all this is now this publication.
- What links your current discoveries to the Science article?
- 2019 was an exceptional year for the Niri Group, with two Science articles published. Our current discovery is a further reflection on the first. In it, Andris Szőnyi and his team showed how quickly and precisely the nucleus incertus in the brainstem can influence the recording of memory traces via hippocampal interneurons. We hypothesized that this brainstem pathway may have more than one role and investigated it further.
We have shown that population-level firing patterns of hippocampal somatostatin-positive cells targeting dendrites, innervated by nucleus incertus neurons, may be able to record and evoke fear memories. This implies that by innervating these hippocampal cells, the nucleus incertus helps to recall fear memories. To this, we must add that these brainstem incertal neurons are under the strong control of higher cortical areas that are also involved in memory functions! This also helps memory.
-How can you summarise this briefly for non-experts?
- We have uncovered a previously unknown neuronal pathway that originates in the cerebral cortex, involving the nucleus incertus, which helps to capture and evoke fear memory traces in the hippocampus.
- The discovery of a pathway, and an important pathway at that, is a very significant discovery, congratulations to all of you! It seems that the search for fear has brought you nothing but "good" so far!
- Basically, we do not always focus on fear. Since I've been working in the group, we've been looking at the functioning of the subcortical pathways, mainly originating from the brainstem, and their role in higher-order functions (memory, recall, emotions). Our results so far show that the brainstem pathways we study encode a kind of emotional-emotional component. Since this can be either negative or positive, it is, therefore, appropriate to investigate behavior triggered by a strongly negative experience. Memory processes are also often tested using conditioned fear behavior tests. These explain why fear was chosen as the topic of our present study.
- Have you used any experiments, techniques, or animal models in your current studies that you have not used in your previous experiments?
- It is always part of science to improve and refine existing techniques, as well as to try new ones. This was no different. I've tried many new viruses, learned behavioral techniques, and perfected them as we've done more and more experiments. I had great help from Kata Sós and Peti Papp, as well as from our TDK students Áron Orosz and Réka Sebestény. During the experiments, I was also able to learn about techniques that provide information about the activation of neurons. With the help of Albert Barth and Erik Misák, we were able to verify the function of the investigated pathways with in vivo electrophysiological experiments and Marci Mayer's analysis of a c-Fos neuron activity signaling experiment demonstrated the activation of a larger population of neurons during the recall of a fear memory.
- You have convinced all those who know the subject that you have investigated it thoroughly and in many ways, and those who don't know it, may be impressed by just the names of the procedures and techniques that they are unfamiliar with.
What would it take to convince both camps of the need for a detailed study of this route?
- There are few known neuron populations in the brain that are located below the cortex and bypass the thalamus to directly innervate the cortex. There are perhaps even fewer that selectively innervate certain cortical regions and only certain neurons within them. One such population of neurons we have identified is in the nucleus incertus of the brainstem. These incertus cells have been shown to be innervated by higher cortical areas (e.g., medial prefrontal cortex, anterior cingulate cortex, and retrosplenial cortex).
This kind of cortico-brain stem-cerebral cortex connection is actually a rarity in the mammalian nervous system. Moreover, our functional experiments have demonstrated that these pathways play an important role in the formation and recall of memories. Evolution may have preserved this pathway system to enable organisms to record a threat stimulus as quickly and efficiently as possible and to inform themselves as quickly as possible of the approach of a potential threat.
- To what extent can what you have found be applied to humans?
- In primates, it has now been shown not only that the nucleus incertus in the brainstem innervates the hippocampus, but also that it innervates the same regions as in mice. In humans, the existence of neurons in the nucleus incertus and its characteristic peptide receptor has also been described. It appears to be a conserved pathway both anatomically and chemically, so it is hypothesized that its function may be similar in humans as in mice.
- The first and last authors in any communication should play a prominent role in the creation of a work. What has been your most significant contribution to this result, apart from a lot of experimental work?
- The ideas that, after reading and summarizing many articles in the memory literature and thinking about them further with Gabor and the group members, finally resulted in an experiment with good results!
- That you enjoy the research is obvious. What do you like most about it?
- All of it. Everything from reading the latest scientific findings and papers to evaluating experiments. I love reading about new scientific results, sharing them with others, brainstorming, using them to devise, design and carry out new experiments, and if something doesn't work out the way we wanted, then rethinking it. I like to discuss neuroscience topics with my topic leader, Gábor, but also with my colleagues or at a conference with people with similar interests, because I think these discussions help broaden our horizons.
- You graduated as a medical doctor, with the most beautiful degree possible, but it seems you will not be a practicing doctor. . .
- As a third or fourth-year student I already knew I wasn't going to practice because I was more attracted to basic neurobiological research than any clinical medical profession. As I received a lot of positive reinforcement as a TDK student, it became clear that I would choose a research career.