Neurons sync their beats like clocks on the wall

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The latest discovery by Balázs Hangya's group, published in Cell Reports, confirmed the existence and role of Huygens synchronization in the medial septum and hippocampus.  

 

Galileo Galilei is credited with the saying "Measure all that can be measured, and what cannot be measured, make measurable." Few pieces of advice have been better received than this, since even the measurement of scientific performance has become a science nowadays, under the name of scientometrics - though for the greatest of them it is useless.  For those interested in science, and even more so those who practice it, know who the greatest were and are.

The Dutchman Christiaan Huygens (1629-1695), recognized by his contemporaries as a physicist on a par with Newton, who was 13 years his junior, and even considered superior in some areas, was unrivaled among the greatest of his time for his many talents (not counting his legal training and his ability to play the cello, ride horses, dance and sword. He had an unrivaled talent for mathematics and is considered the first theoretical physicist and one of the founders of modern mathematical physics, for he used mathematical models to explain physical phenomena. As a physicist, he pioneered the fields of optics and mechanics, and if his mathematical theory of light was rejected in his day, it was accepted a hundred years later thanks to Fresnel's results and has been taught as the Huygens-Fresnel principle.

As an astronomer, among other things discovered Titan, Saturn's first moon, wrote papers on Saturn's rings, developed a two-lens telescope (also known to reduce scattering, and measured the length of the Martian day in less than a half an hour difference, in addition to discovering binaries, nebulae and other celestial phenomena. The list of his results and discoveries could go on, but let's stick to the time that needs to be measured and the accuracy is of utmost importance. Even in antiquity, there were great devices for measuring the time that is still in use today in some places including the sundial clock and the more accurate water clock. However, the clock that until the 1930s was the most accurate was invented by Huygens. And that clock was the pendulum clock. Its importance and usefulness are shown by the fact that poor Huygens patented it in vain, it was produced in France without the patent being accepted, and in Rotterdam and London, it was simply copied. It was big business for them, and not for Huygens, moreover, what he intended as a scientist, the pendulum clock did not work. He wanted to make an accurate timekeeping device for positioning at sea, but the powerful moving of the ocean was an invincible obstacle.

This was certainly a disappointment for him, but it didn't stop him from noticing something very special. The two pendulum clocks on the beam, which had originally been beating out of sync, began to align and eventually beat in sync.

 

But Huygens' synchronization is much more important than just admiring it as a special phenomenon. Three hundred and fifty years after Huygens's original observation, Balázs Hangya and his research team showed and confirmed that similar synchronization can also be achieved by special neurons in a deep brain structure called the medial septum (septum medialis). These neurons form a rhythm-regulating network, also known as a pacemaker network, which generates a 4-12 Hz theta rhythm in the hippocampus responsible for recording the traces of the events we experience, i.e. encoding episodic memory, but the exact mechanism of its generation is not yet known.

The finding is more than a nice result in basic research. The brain's synchronization mechanisms can break down in disease, leading to memory problems and attention disorders, and can also contribute to the development of serious conditions such as schizophrenia, and a better understanding of how brain networks synchronize could therefore help to improve the treatment of serious diseases.

 

The electrical activity of nerve cells has been known since the end of the 19th century, and since the 1930s the use of the EEG (electroencephalograph), created by the Austrian psychiatrist Hans Berger, has been widespread for measuring the electrical activity of the brain. Adding that we have known about pacemaker neuron networks for at least twenty or thirty years, what is the reason for the delay in identifying Huygens' synchronization?

 

Balázs Hangya, head of the Systems Neurobiology research group and corresponding author of a paper published in the prestigious journal Cell Reports, has the answer:

- To understand how the cells of the medial septum synchronize, it makes sense to record the activity of several cells at once. This is not necessarily easy for a deep brain structure but has nevertheless been technically possible since the early 1970s. Nevertheless, in the case of the medial septum, the first such article had to wait until the late nineties. This was noted by John O'Keefe and colleagues, but they were interested in completely different questions, mainly to confirm previous experiments on theta rhythm induction under anesthesia in awake animals, and did not investigate the activity of the cells in relation to each other. We started working on this with Viktor Varga around 2009, and over a period of almost 10 years, we collected a lot of data from anesthetized and awake rodents. It is still a challenge technically that in addition to deep brain multichannel drainage, an electrode placed in the hippocampus is absolutely necessary to understand the output signal of the medial septum, so the surgeries can only be performed by professional operators. 

Optogenetic identification of several cell types has also been performed, but this technique only became available in the two thousand and ten years

 

 - Who carried out these complex experiments that required not only knowledge but also great skill?

 

- The anesthesia experiments were carried out by Richárd Fiáth and myself, the conduction in awake mice by Andor Domonkos, and the optogenetics experiments by Sergio Martínez-Bellver.

 

- Experiments are performed using a variety of anesthetics. Why did you choose urethane?

 

- Theoretically, theta activity is mainly well measured in urethane anesthesia, so this is the "textbook" model, we have not tried anything else.

 

- Only about half of the optogenetically identified parvalbumin-positive (PV+) cells were found to belong to the rhythm regulatory network. What is the role of the rest?

 

- Among the PV+ cells, not only pacemakers were present in high numbers (only about 13% in the whole population), but also cells that always reflected hippocampal activity. We called these "follower cells". We show in the paper that these cells are often synchronized with the population called pacemakers, so I think these cells may also be involved in some way in the triggering of the theta rhythm.

However, this is speculation, for now, future experiments are needed to confirm or disprove this theory.

 

- In addition to PV cells, another important group of cells in the medial septum, the glutamatergic cells (GLUT MS), have also been investigated. What is the role of these cells?

 

- The firing rate of GLUT MS cells is increased at the onset of theta stages. From previous anatomical work, we know that these cells provide the main stimulatory innervation to the GABAergic cells of the medial septum. Because GABAergic cells are inhibitory cells, GLUT MS cells may be the ones that switch the inhibitory cell network to a more active state, thereby facilitating Huygens synchronization.

 

- Species-dependent differences in firing were also found among the MS pacemaker cells studied. What do you think about the significance of this variation?

 

- The greatest difference was observed between mice and rats when the hippocampus did not show theta activity, i.e., medial septal cells did not generate theta synchronization. When this was the case, the rat cells showed a slower (delta) rhythm, whereas the mouse cells showed an asynchronous firing without rhythm. The reason for this is not yet understood.

Interestingly, there were also minor differences in the function of some cell types during synchronization. Based on a principle formulated not so long ago, it is possible that although the theta wave itself is evolutionarily conserved, larger variations in the exact cellular mechanism are allowed.

It would also be good to have an answer to this in the future.

 

- Huygens devised a simple mathematical model for each of the phenomena he studied, changing it as necessary as he went along. You also used a computer model, now known as an in silico experiment. Your model was deliberately significantly simpler than what you tested in vivo, but the results showed what you measured in vivo. One could interpret this to mean that since this simpler system knows what you measured in vivo, what you claim must be true.

 

- No, it is not! Occam's razor should be shaved with care.

What the model certainly shows, however, is that a single "cell type" can be sufficient to generate a theta, so subpopulations "ping-ponging" with each other are not a necessary condition for synchronization as previously thought. Of course, we know that there ARE multiple cell types in the septum, and this model does not explain what this means for rhythmicity. Models are usually an attempt to understand a selected aspect in a simplistic way, rarely aiming to be "realistic" in all aspects.

 

 

The work published in an article is the result of a collective effort of a team, where everyone is responsible for the whole, but the distribution of tasks and the burden are not equal between team members.  The last author of the article has the biggest task and responsibility, he is in charge, and is usually expected to raise the funds for the research. How did Barnabás Kocsis, the first author of the Cell Reports paper, get involved in the team, and what was his main task? 

 

Barnabás Kocsis

- I finished my second year of bionics at Pázmány ITK in two thousand and fifteen and wanted to get acquainted with the world of research, so I joined Balázs Hangya's lab, which was starting up at the time.

I was given a few topic ideas, and the one I liked the most was "the emergence of network synchronization". I started to analyze the recordings in the anesthetized rat, and gradually added the other data sets and modeling. Such a large amount of data is not easy to manage together, especially when you don't know what the exact expectations are at the beginning. One tries to find general principles and natural parameters with as few arbitrary and ad hoc choices as possible. Often, changing a critical value can lead to quite different results, and this is not trivial to filter out. Finally, an open Matlab package of a few thousand lines was put together, which can be run semi-automatically on completely new data with minor changes. This is what we used in the article.

 

- You have made a significant discovery. What do you consider to be the biggest success and what further experiments or results might follow now?

 

- We have succeeded in coming up with a new idea for the generation of network synchronization. The fact that PV+ cells in the medial septum become frequency synchronized upon amplification of local glutamatergic inputs was previously unknown.

It would be interesting to investigate this more closely from aspects such as whether this is a necessary/sufficient condition for the generation of theta waves, or how it relates to the amplitude and frequency of hippocampal theta.

It is also an intriguing question to what extent the rhythmicity groups we have defined form stable, well distinguishable classes, if there is a crossover between them, what is the relationship between this, and does it carry a function?

 

- Do the results so far allow us to start some kind of human experiment?

 

- In a basic research project, is all about accumulating knowledge. We describe the state-dependent behavior of rodent cells in one brain area and provide a tool to analyze other data sets efficiently. We adopt a model for the observed network behavior. This model can then be further investigated and extended using mathematical methods.

Since Huygens's synchronization of oscillators is a well-described phenomenon in physics, these observations can be tested and used in biology. At this point, we can let our imagination run wild. It would be interesting, for example, to study the development of hyper synchronization in epilepsy or the oscillopathies associated with synchronization errors, such as the frequency mismatch that accompanies schizophrenia.

 

Hippocampal theta oscillation in the anesthetized rat. Electrophysiology recording by Balázs Hangya, visualized by Barnabas Kocsis. 

 

Barnabás Kocsis, Sergio Martínez-Bellver, Richárd Fiáth, Andor Domonkos, Katalin Sviatkó, Dániel Schlingloff, Péter Barthó, Tamás Freund, István Ulbert, Szabolcs Káli, Viktor Varga and Balázs Hangya : „Huygens synchronization of medial septal pacemaker neurons generates hippocampal theta oscillation”. Cell Reports Aug. 2. 2022

 

 

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Kocsis et al, Cell Reports 2022

Kocsis et al, Cell Report 2022
Kocsis et al, Cell Reports 2022
Kocsis et al, Cell Reports 2022