Thunderstorm in the brain or when lightning strikes the same place twice
Our memories about space and time are encoded in a small part of our brain called the “hippocampus”. When you try to find your way to a hotel in a city unknown to you, drive your car to work almost automatically, or catch small cute monsters on your way home — nerve cells in the hippocampus generate bursts of small electrical discharges — “spikes” in a manner unique to the place you are, the path you’re taking and your memory about the things around you. Interestingly, this is true for not only the real world, but also virtual spaces, such as those generated by computer games. By using tiny electrodes, nowadays neuroscientists can record these electrical spikes and even feed them into normal PC speakers playing “brain music” in real time. Place-specific nerve cell firing was first discovered decades ago, and in 2014 John O’Keefe, May-Britt Moser and Edvard I. Moser shared Nobel Prize in Physiology and Medicine for this discovery.
The hippocampus itself is not a homogenous bunch of nerve cells. It has long been widely accepted, that hippocampus consists of sub-areas called CA1, CA2, CA3, CA4 and DG. Why these five? Well, simply speaking because they look differently under the microscope. However, looking different (especially when you already under the microscope) does not imply behaving differently in more naturalistic circumstances. Many attempts to decipher the functional role of the hippocampal sub-regions yield in hundreds of scientific papers about CA1, CA3 and DG, while CA2 and CA4 were almost forgotten. Why? Well, maybe because CA2 is quite small and located between CA1 and CA3, so it was considered as transient area, kind of “dross of evolution”, and CA4 is still being called the “deep, polymorphic layer of the DG”, according to Wikipedia, Theodor Blackstad (1956) and David Amaral (1978).
In 2011, Dr. Matt W Jones from University of Bristol and Dr. Thomas J McHugh from RIKEN Brain Science Institute wrote a review paper about CA2 titled “Updating hippocampal representations: CA2 joins the circuit”. The paper was published in scientific journal “Trends in Neuroscience” (Cell Press), with intent to trigger attention of researchers to the CA2 area and its possible role in regulating of hippocampal activity. During the following years a few labs have reported new discoveries about CA2, including its possible role in social recognition/interaction (Frederick L. Hitti and Steven A. Siegelbaum, Nature, 2014).
In our lab we were trying to answer even more general question — what will happen with the brain if we turn CA2 off? The naive answer would be “almost nothing, because CA2 is too small, so its presence doesn’t matter”. OK, let’s turn it off and check it out! Easy to say… Our current understanding of how brain works is quite limited. What we know more or less confidently, is that at the real time scale information propagates throughout brain circuits as electrical impulses, settling down later in molecules as long term memory. By using sophisticated genetic manipulations neuroscientists can block propagation of such information precisely in the targeted brain area, in reversible manner, and without physical damaging the brain cells.
Our attempt to shut down CA2 area in mice had led to quite unexpected results. While normal place-specific activity of neurons occurred as usual, sometimes, in some specific places, an electrical burst so strong that it can be compared to an electrical storm swept throughout the whole hippocampus. The surprise of seeing this phenomenon was also supported by the fact, that according to previously published research results, turning off other areas of hippocampus did not cause such discharges. The only known event similar to what we saw is a brain undergoing epileptic seizure. Such seizures however, known to occur at random times and not related to any particular space. Does the lack of CA2 functionality somehow related to epilepsy? It’s an open question, but the place-specific seizures (or “pleizures”, according to Thomas J McHugh) we found, remind me a weather phenomenon known as “Catatumbo lightning”. The area surrounding the mouth of the Catatumbo River in Venezuela experiences an average of 250 lightning flashes per square kilometer annually, earning it the title of the “most electric place on Earth” and disproves the old adage “lightning never strikes the same place twice”. If an epileptic seizure can be seen as a thunderstorm somewhere in the brain, — then hippocampal network without CA2 results in location dependent triggering of epileptic-like discharges much like the unique and not well explained atmospheric conditions above the Catatumbo delta make it an ideal place for thunderbolts.
This article was written by Denis Polygalov with support from Thomas J McHugh and released under the Creative Common Attribution–ShareAlike License (CC BY-SA 2.0). Original photo of the Catatumbo lightning by Fernando Flores. The photo was modified by Denis Polygalov.
Reference: Roman Boehringer, Denis Polygalov, Arthur J.Y. Huang, Steven J. Middleton, Vincent Robert, Marie E. Wintzer, Rebecca A. Piskorowski, Vivien Chevaleyre and Thomas J. McHugh, Chronic Loss of CA2 Transmission Leads to Hippocampal Hyperexcitability Neuron, Volume 94, Issue 3, p642–655.e9, 3 May 2017, DOI: http://dx.doi.org/10.1016/j.neuron.2017.04.014
Photo credit: ferjflores via Visualhunt / CC BY-SA
