Memory multiplex

Life is good, says the film title and claims the perfume brand (La Vie est Belle, Lancome), and there are times when we are eager to prove it right. Fewer probably feel what John Keats' poem "Ode on a Grecian Urn" adds:

"Beauty is truth, truth beauty- that is all
Ye know on earth, and all ye need to know".

To know something is true, or to feel it is beautiful, often seem to be two different things, but mostly it just means that we don't see the beauty in something, or we don't understand the truth of something.
Here, for example, is the latest work of Balázs Hangya and his team, published in Nature Communications. According to Bálint Király, they have investigated a question in the brain that engineers began to address 150 years ago.  This is beautiful in itself.

- I would never have thought that telecommunications as a term existed back then, but the fact that it never occurred to them to consider it in the brain is quite understandable.
- Indeed, and astonishingly, it seems that the brain employs all three of the telecommunications that have since become fundamental in a highly complex system, as it multiplexes space (e.g. analog stereo audio cable) time (e.g. digital telephony) and frequency division (e.g. radio) simultaneously.

- All three solutions could have won a Nobel Prize! (To be precise, Marconi was awarded the Nobel Prize for the invention of the radio, shared with Karl Ferdinand Braun in 1909, although after Marconi's death, it was taken from him and awarded to Tesla, who also died by then and died as a poor, while the already wealthy Marconi was so successful with the wireless telegraph that he became even richer, although he did not invent it first either, Popov did 4 years before him.)
But let's stay with the hippocampus, which we already know a lot about in terms of learning and memory. What's the trick to this amazing feat?
- In the hippocampus, there is a slower brain wave (theta) that switches between memory write and recall modes in time, which are encoded in faster (gamma) waves of different frequencies from spatially separated inputs. This solution seems to do the job extremely well, as we can usually easily recall and recount the route we took last night while walking, while also memorizing the current route and not getting lost!

- And is this due to the alternation of slower and faster waves in the hippocampus?
- Only partly! Although the brain switches between saving and recalling about eight times a second (so that this switching is not really conscious and seems to be completely parallel), it also requires the whole network to work in perfect harmony!

- This in itself shows that you have found something else, and that is the real discovery. But where did you start from and where did you end up?
- We started from the lab of Tamás Freund, more precisely from the results of the research topic started there. It was there that Balázs Hangya and Viktor Varga started to investigate the relationship between the medial septum and hippocampal theta waves, and their work has already given us a lot of information about the important role of the septum, and especially the so-called pacemaker (rhythm-regulating) cells and their synchronization mechanisms in the generation of hippocampal theta.
These cells are characterized by a robust periodic activity of about 8 Hz rhythmicity, which corresponds to the theta frequency, but a largely overlooked feature of this activity is that 8 times per second, they are followed not by simple action potentials but by gamma frequency (30-150 Hz) action potential bursts (in jargon, bursts).
This is very similar to the activity pattern in the hippocampus during memory processes, so I first started to investigate these signals.
The lesson of the analyses is that this parallel is not accidental: the medial septum is much more than a simple metronome dictating the tempo of the hippocampal theta rhythm. It is more akin to a conductor conducting a symphony of oscillations over a much wider frequency band and is an organic, living, bidirectional contact with the entire hippocampal orchestra. This allows him to ensure that memory storage and retrieval through hippocampal structures and the entorhinal cortex can occur with perfect timing.

- I like this analogy very much and it is certainly not only musicians or concert-goers who understand it perfectly. So the medial septum controls what happens in the hippocampus, and certainly has as good a view of the neurons to be controlled as the conductor has of all the members of the orchestra. What's more, this "insight" is, I suppose, reciprocal there too.
How could you prove it, what helped?
- The bulk of the article is a re-analysis of five previous experiments for other projects using this new approach. It all started as a short little analytical side project on the data from the first experiment and frankly, we didn't expect much from it, but after the first rather unexpected observation - that hippocampal gamma activity is not only represented in the medial septum but also appears earlier in time, suggesting a septum -hippocampus directed causality - each experiment analyzed opened up new questions about the nature of the network. Balázs always knew where to turn for the data to answer this, which is how this huge data set was finally assembled and the whole puzzle was put together.

- The analyses require time-consuming, careful work, professional knowledge of the necessary mathematical apparatus, and certainly much more. Who was involved in this work?
- I have to highlight the contribution of Andor Domonkos, because the most important exploratory results are based on his data, but some of the data series were recorded by Balázs (Hangya) long before he became a team leader. I am in the fortunate position that I did not have to do a single new experiment for this project!

- How is that possible?
- We needed the optogenetic and electrophysiological expertise of Márti Jelitai and Dani Schlingloff for the experimental testing of our hypothesis for the revision of the article. Although as a physicist (originally) I now do almost all analysis and modeling, I used to do a lot of experimentation, so I know the hard work behind the data, and it was particularly enjoyable in this project to have a large part of the data quasi-recycled.

- It's up to date with the latest trends!
- That's one way of putting it, but even so, I worked on this project for a total of 5 years, as the nature of the question required a bit more complex analysis than usual.
- There are more authors than those mentioned so far. . .
- And I am grateful to all of them. Sergio Martínez-Bellvere, Barnabas Kocsis, Abhilasha Joshi, Minas Salib, Richárd Fiáth, Péter Barthó, and István Ulbert for sharing their experimental results with us.
And I feel particularly fortunate to have been able to re-analyze the quite extraordinary - and certainly heroically fought-for - database of the former Somogyi Lab.
I do not exaggerate when I say heroic struggle, because not only was the electrophysiological activity of 32 septal cells recorded simultaneously with hippocampal waves, but we also reconstructed their almost complete projection structure. It's a real goldmine and has helped me a lot in mapping the network behind the process. Indeed, these data revealed that the septum, in addition to direct projections, also uses indirect pathways via the hippocampal CA3 region and the entorhinal cortex, which modulate spatially, temporally, frequency - and, according to prevailing theories, memory function - distinct gamma activities in CA1, as confirmed by our optogenetic experiments.

I had the opportunity to work with Tim Viney, Vítor Lopes-dos-Santos, and David Duprett (Oxford) on these recordings, which was very inspiring and for me, and beyond the results, a particular value of this project.
Overall, it has been an extremely rewarding project from which I have learned a lot.