An international study led by researchers from the Institute of Neurosciences (Spain) in rodents described the changes in the organization of the genetic material of neurons triggered by neuronal activation, in both pathological context (epilepsy) and physiological (learning and memory formation).
The results show that some of these changes are stable and can be detected even days after neuronal activation, as a form of genetic memory of the past activation.
The work, published in the journal Nature Neuroscience, reveals 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 describe for the first time the changes that take place in the genetic material of the hippocampal excitatory neurons of adult mice when activated.
“We wanted to know how the activation of a neuron changes its own future response, which constitutes a form of cellular memory essential for the formation of memories,” explains Ángel Barco, from the Institute of Neurosciences, a joint center of the Higher Council for Scientific Research (CSIC) and Miguel Hernández University.
“For this we have used several neurogenomic techniques that are applied for the first time in an intact mouse brain,” he says. Specifically, the authors wanted to know what happens in a neuron that is activated when we are in a novel context.
“This is important for memory formation, but it is very difficult to address experimentally. When we focus our attention on something concrete, a very small group of diffusely distributed neurons in the brain is activated and it is difficult to select them and see what happens inside,” adds Barco.
A shortcut to study memory
The researchers took a shortcut. They caused massive activation of mouse neurons, as in an epileptic process, and have looked at the changes taking place in chromatin.
Chromatin is the highly compacted form in which the almost two meters of genetic material (DNA) is stored in the tiny nuclei of the cells thanks to the action of special proteins called histones – about one hundred pins fit thousand cell nuclei.
“The advantage with the epilepsy model is that we have a lot of starting material. It is easy to have 10 million cells. If we want to go to the most complicated memory model, only scalable techniques with little starting material will work for us,” says Barco.
The researchers were subsequently able to confirm the changes observed in the epilepsy model in an everyday situation, such as the activation of groups of neurons that take place in the brain of a mouse when exploring a new place.
The researchers saw that in both cases there is a transcriptional ‘explosion’. That is, a very strong activation of specific genes to produce proteins.
Transcription is the first step of gene expression. This stage consists in copying the DNA sequence of a gene into a messenger RNA molecule that will subsequently lead to the formation of proteins, which are the ones that actually direct almost all vital processes.
This epigenetic footprint that persists in chromatin could represent an appropriate substrate for lasting changes in behavior.
It depends, in turn, on the changes that take place in chromatin. The degree of compaction of that chromatin and the interactions between separate regions of the chromatin contribute decisively to regulate transcription and therefore 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 the activation of genes.
“The observed large-scale dynamic adjustments of the genome topology probably contribute to the rapid and coordinated transcriptional response associated with neuronal activation in both normal and pathological conditions,” explains researcher Jordi Fernández-Albert of the Institute of Neurosciences.
These changes (called epigenetic because they do not affect the information contained in the genetic material but their expression) can lastingly or permanently modify the expression and future responsiveness of the genes involved in cognitive function, thus representing a type of genomic memory.
This epigenetic footprint that persists in chromatin could represent an appropriate substrate for lasting changes in behavior, which could participate in the establishment of memories, influencing the future response of neurons to stimuli. In addition, some of these lasting changes could be related to brain disorders such as epilepsy and cognitive dysfunction.
The study has had the participation of researchers from Emory University, in Atlanta (United States).