How are memories formed?

The process of forming memories

Scientists now know that when a new experience forms a long-term memory in our minds, specific neurons encode details that, when reactivated, we will remember. again.

These important neurons are also known as engram cells. Thanks to improvements in technology over the past few years, scientists are now able to zoom in on the details inside the engram cell at higher resolution and closely monitor memory formation.

According to a research paper published in Nature Neuroscience, Professor Li-Huei Tsai's group from the Massachusetts Institute of Technology (MIT) has revealed for the first time that epigenetic inheritance occurs in genetic material within cells. engrams at different stages of memory formation. And large-scale changes in the 3D structure of the genome regulate the expression of specific genes involved in memory storage.

To track the engram cells, the scientists turned their research to specifically genetically engineered mice. Their genomes are tagged with fluorescent proteins, and the cells glow when they express the Arc gene, which is involved in memory formation.

The researchers used mild foot shocks to induce fear memories in specific locations in mice and in the hippocampus in their brains, an area of ​​the brain important for learning and long-term memory. For example, engram cells encoding memory are seen as fluorescent yellow. The researchers then analyzed the glowing cells in detail hours and days after the memory was formed and when the memory was reactivated.

A slice of the whole rat brain, you can see the neurons that light up during memory formation and recall.

During the encoding phase of the memory, they noticed subtle changes in the structure of chromatin in the nucleus. Chromatin is formed by tightly wrapping long strands of DNA and proteins, when epigenetic modifications in certain regions are altered to become looser, exposed DNA allows genes on it to easily "read".

But they were surprised to discover that the loose regions were not coding gene fragments, but instead contained noncoding sequences called "enhancers". These sequences serve specific genes and help turn them on.

Over the next 5 days, during the memory consolidation phase, more changes took place in the 3D structure of the surrounding chromatin enhancers, and more enhancers moved closer to the genes they served.

So far, however, gene expression in the cells has not changed as dramatically as the researchers expected, a result that, in the words of first author Dr. Asaf Marco, has disappointed them. .

During memory formation, the 3D structure of the chromatin is altered, bringing the enhancer closer to the site where gene expression begins.

Next, the researchers returned the mice to the environment in which the memories were originally formed. When memories are revived, gene expression takes place rapidly. Many genes activated by the enhancer are involved in the synthesis of synaptic proteins, leading to stronger connections between neurons rapidly forming.

"Only then did we realize that previous structural changes in chromatin were preparing cells for memory enhancement during the recall phase," said Dr. Marco. Another expert commented on the process of memory formation: "It's like a warm-up before a workout, they - the engram cells are ready to go, so we can start recalling."

During recall, proteins involved in memory storage are produced in large quantities, and connections between neurons are strengthened.

Dr Marco concludes: "This study shows for the first time that memory formation is promoted by the stimulation of gene expression during the recall phase by enhancers that begin with epigenetic modifications." .

What is the mechanism of long-term memory formation?

Scientists at Harvard Medical School tried to solve this mystery more than half a century ago, with their findings published in the leading academic journal, Nature.

Let's turn back the clock to 1986. At that time, Professor Michael E. Greenberg, the corresponding author of the study, had just arrived at Harvard University.

In one study, he and his colleagues found that once a neuron is activated, it begins to express a gene called Fos for a short period of time. Although the Fos gene encodes a transcription factor, the scientists don't know what it's actually doing, but they think it's used as a marker for neuronal activation.

However, the expression patterns of Fos suggest that it is most likely involved in some of the neuronal functions that influence our ability to learn and remember.

To test that idea, in this study, the scientists placed mice in a new environment and assessed the activity of key neurons in their hippocampus. Strangely, the neurons expressing the Fos gene did not clump together after exposure to the new environment, instead they were scattered all over the place.

Could this also affect memory formation? Subsequent research confirmed this. After inhibiting the Fos-producing neurons, the mice experienced significant memory impairment and became trapped in the maze and had difficulty getting out. This also suggests that Fos-expressing neurons are indeed involved in memory formation.

After exposure to the new environment, the hippocampal neurons expressing the Fos gene (red) were not concentrated but scattered everywhere.

Using optical genetics, the scientists activated other neurons around these neurons and discovered that they were influenced by two types between neurons: The former inhibitory signal transduction is enhanced and the other is weakened.

If the neuron itself did not express Fos, it would not have the same properties. In addition, the relationship between the activation of these neural signals and other neurons in the loop is also important. The researchers note that Fos may be related to the ductility of specific turns of wire. Since Fos is a transcription factor, researchers naturally thought of analyzing the other genes it controls.

Using methods such as single-cell sequencing, they identified an important gene called Scg2, which affects inhibitory signaling. If the Scg2 gene in mice were inactivated, the Fos-activating neurons would develop defects in signal reception.

Correspondingly, the mice also had problems with brain waves related to learning and memory. Specifically, Scg2 encodes a neuropeptide that is divided into four different forms. Researchers have shown that neurons use these neural chains to fine-tune signals from neurons.

Taken together, the scientists propose a model: when exposed to something new, a small cluster of neurons in the hippocampus simultaneously express Fos, activate the Scg2 gene, and produce neuropeptides corresponding. After receiving instructions from interneurons, these neurons form a coordination loop.

"When neurons in the hippocampus are activated, they don't need to be connected in a special way before. Neurons between neurons have very wide axial branches that can connect. with many cells at the same time and transmit signals. It is possible that these isolated neurons are internally connected," the team said.

This study presents the mechanism of long-term memory formation from a molecular perspective. Whether it's to study basic biology or memory-related diseases, it matters.