Researchers Describe Epigenetic Fingerprints That Daily Experiences Leave in Neurons

An international study conducted by researchers from the Instituto de Neurosciencias, UMH-CSIC in Alicante, presents a new multi-omic analysis of changes in the organization of neuronal genetic material triggered by neuronal activation both in a pathological context (epilepsy) and physiological (learning and memory).

Some of these changes last a long time and can be detected even a few days after neuronal activation, in the form of a genomic memory of past neuronal activation.

Research, conducted in rodents and published in Nature Neuroscience, shows new molecular mechanisms that contribute to the plasticity of the adult brain. The changes initiated by neuronal activation are more complex and act at more levels than previously thought.

These findings, made by an international team led by researchers from the Instituto de Neurosciencias, UMH-CSIC in Alicante, with the participation of researchers from Emory University in Atlanta, describe for the first time the changes that have occurred. in the organization of genetic material in the hippocampus. excitatory neurons of adult mice during activation.

"We wanted to know how the activation of a neuron can change its future response, these changes are a form of cellular memory essential to the formation of memories," says Dr. Ángel Barco, researcher at the university. Institute of Neuroscience UMH-CSIC, directed research. "To achieve this goal, we used several neurogenomic techniques applied for the first time to an intact mouse brain," said Dr. Barco.

The researchers wanted to know precisely what happens in a neuron that activates when the animal is exposed to a new context. "This answer is important for the formation of memory, but it is very difficult to approach experimentally.The group of neurons that respond to such an experiment is a very small group, diffusely distributed in the brain, so it is very difficult to isolate them and see what's going on inside, "adds Dr. Barco.

For simplicity, the researchers took a shortcut. They caused massive activation of mouse neurons, as in an epileptic process, and examined changes in chromatin.

Chromatin is an extremely compact structure in which nearly two meters of genetic material (DNA) is stored in the tiny nuclei of cells through the action of special proteins called histones. To get an idea of ​​the degree of compaction of chromatin, about one hundred thousand nuclei of cells fit on the head of a pin.

"The advantage of the epilepsy model is that we have a lot of starting material to perform the analysis.It is easy to have 10 million cells.If we want to switch to the model the most complicated memory, only scalable techniques requiring little starting material will work, because in this case, the neural network is formed of about 2000 cells, "says prof. Barco.

"With what we have learned in the simulation of epilepsy, we have been able to confirm these changes in a more physiological situation, such as the activation of neuronal groups that take place in the brain. a mouse when exploring a new place, "he said. added.

The researchers found that in both cases a transcriptional "burst" occurred. This is a very strong activation of specific genes to produce proteins. Transcription is the first step in gene expression. This leads to the formation of proteins, molecules that drive almost all life processes.

In turn, the transcription of genetic material depends on the changes that occur in the chromatin. The degree of compaction of this chromatin and the interactions between distinct regions of chromatin contribute decisively to the regulation of transcription and thus to gene expression.

This study demonstrates that this activation is associated with an increase in accessibility and the appearance of new interactions between separate regions of chromatin, necessary to allow gene activation. "The dynamic and large-scale adjustments of the genome topology observed in our study probably contribute to the rapid and coordinated transcriptional response associated with neuronal activation under normal and pathological conditions," says Jordi Fernández-Albert, the first author of the study.

These modifications, termed epigenetic because they do not affect the information contained in the genetic material but their expression, can permanently modify the expression and the future response capacity of the genes involved in cognition, thus representing a type of genomic memory. .

These epigenetic fingerprints in chromatin may be an appropriate substrate for lasting behavioral changes. They could participate in memory building by influencing the future response of neurons to the same stimuli that caused the change or different stimuli. In addition, some of these lasting changes could be related to brain disorders such as epilepsy and cognitive dysfunction.

Provided by
National Council of Spanish Research