02/22/2016

Aggression causes generation of new brain cells, MIPT researchers discover

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Stem cells (green) in the granular region of the dentate gyrus of the hippocampus (nucleus of the dentate neuron are red). The photo has received an award at BioArt and is featured in the Scott Gilbert "Developmental Biology"; image courtesy of Grigori Enikolopov

A group of neurobiologists from Russia and the USA, including Dmitry Smagin, Tatyana Michurina, and Grigori Enikolopov from MIPT, have proven experimentally that aggression has an influence on the production of new nerve cells in the brain. The scientists conducted a series of experiments on male mice and published their findings in the journal Frontiers in Neuroscience.

Researchers from the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences (ICG SB RAS), MIPT, Cold Spring Harbour Laboratory, and Stony Brook University and School of Medicine studied the changes that occurred in the brains of mice demonstrating aggressive behaviour, which attacked other mice and won in fights. After a win, these mice became even more aggressive, and new neurons appeared in their hippocampus – one of the key structures of the brain; in addition to this, in mice that were allowed to continue fighting certain changes were observed in the activity of their nerve cells. The scientists hope that the new information on the neurobiological bases of aggression will not only help in understanding this important phenomenon, but will also encourage research in other areas – and even help in finding causes of autism and other similar disorders in humans.

In order to explain exactly how aggression affects the formation of new neurons, how it alters the functioning of the brain and what autism has to do with all of this, we need to take a careful look at various aspects of the recently published study.

“Once again I am amazed at how the basic building blocks that make up complex behaviour are similar in different organisms and it is truly fascinating how they can be combined with other blocks to create an enormous variety of behavioural reactions in animals and humans,” said Grigori Enikolopov, the head of MIPT’s Laboratory of Brain Stem Cells and corresponding author of the study.

How? At behavioural level

This is how the experiment itself was conducted: pairs of male mice were placed in a cage bisected by a partition. The partition allowed the animals to see, hear, and smell each other, but did not allow physical contact. Every day, in the early afternoon, the partition was removed and the observations began: it did not normally take long for fights to break out. After two or three encounters the winner was established and was then (after three minutes, or sometimes less to avoid injuries to the defeated male) separated from its neighbour again. After repeating the process for three days in a row, the scientists changed the mice in the cages, randomly placing defeated males with a new neighbour (but, most importantly, each time a defeated male was placed in the same cage as another winning male). In one group, after three weeks of these rotations, winners were prevented from entering into confrontation, and in another group the mice continued to fight with one another.

The scientists also conducted a series of tests to demonstrate the effect of aggression not on the brain, but on behaviour. For example, the mice were placed in a cross-shaped maze (plus-maze) where one corridor was closed and the other was an open space. The more time that the mice preferred to spend in the dark, closed space, the more their behaviour could be described as “avoiding risk”.

The mice were placed in a cage with a transparent partition and another male on the other side – the more time the mice spent close to the barrier, the higher the level of potential aggression. This interpretation is consistent with the fact that the active animals in the study tend to attack their partners if the opportunity arises (tests were also performed to prove this).

Line is a more rigorous concept than “species”. A line is all the mice produced by the inbreeding of the offspring of one pair of mice with the same genotype. The C57BL line is one of the most common. And incidentally, BL stands for black – so laboratory mice are not typically white!

All the tests showed that males with winning experience in a number of fights display a more “brazen” attitude – they approach the transparent partition more often and initiate an attack on their opponents more quickly. If the mice were deprived of fighting for a period of time before the test, they became even more aggressive: the latency to the first attack was almost three times less, and the fights themselves lasted for longer. But what is particularly interesting is that at the same time their level of anxiety increased – a male who succeeded in tearing out patches of hair from the back of a weaker mouse would rather avoid open spaces, preferring to sit in the dark wherever possible!

Mice of different lines may even exhibit different behaviour when fighting. In a confrontation, C57BL mice normally pull out patches of hair from their opponent’s back. The fights are rarely fatal, but cases of this have been known to occur.

The methods used in the experiments were not chosen by chance. Natalia Kudryavtseva, one of the authors of the study (Head of the Sector of Social Behaviour Neurogenetics at ICG SB RAS), is an internationally recognised leader in the study of the biological bases of aggression, and the behavioural model and method of studying aggression in mice has been developed over a period of decades.


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C57BL male laboratory mice. Image: Alexei Timoshenko.
How? At cellular level

The study of aggression in the context of the function of the brain at the level of individual cells was made possible as a result of the progress achieved in neuroscience in recent decades. Three statements are now considered to be reliably proven:

- Our behaviour, and the behaviour of animals, has an influence on the function of the brain and may cause long-term changes;

- Contrary to the previously accepted view, new neurons can be generated in a mature brain and this process plays a key role in learning;

- In order to initiate long-term changes at cellular level, cells need to activate certain genes and suppress the activity of others.

Despite the fact that DNA is the same in all cells, different sections (different genes) have a different status. If the DNA is chemically modified, or the proteins that combine with DNA to form chromosomes are modified, it is no longer possible to read information from the gene and synthesize molecules encoded by that gene. The cell stops the production of unnecessary proteins, e.g. a neuron does not synthesize the muscle fibres required by myocytes, muscle tissue cells. By controlling the activity of genes, neurons can also rebuild themselves, and activating stem cells in the brain can lead to the generation of new nerve cells – in order to build the neural networks that play an essential role in memory for example.

Studies in the field of the neurobiology of memory, which were first conducted in the mid-20th century, have shown that learning or even simply encountering something new sets off a series of molecular changes in neurons – and certain genes, which scientists call immediate early genes (IEGs), are activated to produce long-term transformations in the brain. If a test sample of an animal’s brain is taken shortly after a learning experiment and combined with special labels of the protein encoded by c-fos, scientists are able to observe the changes triggered by the experiment. This is exactly what the authors of the paper did to trace the effects of aggression at cellular level – monitoring c-fos levels is one of the standard methods of actively searching for changes in nerve cells.

Neuroscience – the study of the brain often requires knowledge in unexpected fields, such as optics, game theory, economics, or sociology. Practical skills employed by neuroscientists often include the ability to manipulate, program, and control rats and make statistical calculations. This is why this interdisciplinary field has been classified separately by British and American scientists as neuroscience.

Where? The hippocampus and amygdala

Simply observing individual neurons, or even groups of neurons, does not give a complete picture. The location of the cells needs to be taken into account. The activity of neurons in different regions of the brain may vary significantly, as these regions perform different functions.

In this particular study, the scientists examined the hippocampus and the amygdala. It is often said that the amygdala is associated with emotions, and the hippocampus with memory, and this is generally true – but it should be clarified that despite this, memory is not localized in the hippocampus, and to experience emotions even mice need more than just the amygdala.

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