Unraveling the genetic mechanisms of long-lasting memories in the brain

A new study is shedding light on how long-term memory is formed in the brain by taking a closer look at molecular and genetic factors. 

Riding your bike without training wheels at three, your first romantic kiss as a teenager –when it comes to recalling long-ago events, how do we do it?

Researchers at Albert Einstein College of Medicine have found the explanation in a paper published online on April 25 in Neuron [1]. One of the most remarkable features of the brain is its ability to learn new information and store it for a long time, noted Robert H Singer, PhD, a co-corresponding author.

The molecular basis for making long-term memories has been discovered in mice, adds Dr Singer, who also heads the Einstein Program in RNA Biology and the Dominick P Purpura Department of Neuroscience [2].

Memory’s cellular basis was already known in some aspects. The hippocampus is a brain region where neurons (nerve cells) store memories. Repeated neural stimulation strengthens synapses, which are the connections between nerve cells.

Proteins help synaptic connections form long-term memories. In turn, memory-associated genes transcribe (copy) messenger RNA (mRNA) into those proteins.

It takes several hours to form a lasting memory, but mRNAs and proteins involved in making proteins disappear within an hour. This was according to Sulagna Das, PhD, first and co-corresponding author of the paper. How is that possible?

This question was answered by fluorescently tagging all molecules of mRNA from Arc, a gene critical for converting our activities and experiences into long-term memories, in a mouse model. Using high-resolution imaging techniques, researchers stimulated synapses in neurons from the mouse hippocampus. Then, they observed the results in real-time in individual nerve cells.

A single stimulus to a neuron caused the memory-coding gene Arc to produce mRNA molecules that were then translated into synapse-strengthening proteins. Some of the protein molecules made from that first synaptic stimulus return and reactivate Arc, triggering another cycle of mRNA synthesis and protein production, said Dr Singer.

In each cycle, more and more protein accumulates at the synapse, where memories are cemented. A previously unknown feedback loop explained how short-lived mRNAs and proteins can create long-lived memories, according to Dr Das.

You can think of it as an intermittent stimulus that adds memory-building protein to your synapse after reading a poem repeatedly, per Dr Singer. Arc gene mutations are associated with memory difficulties in humans and neurological disorders like autism spectrum disorders and Alzheimer’s disease. 

It may be worthwhile to gain insight into the causes of these health problems by studying Arc‘s response to nerve-cell stimulation, Dr Das noted. The research paper is called “Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation”. Additional Einstein authors include Pablo Lituma, PhD and Pablo Castillo, MD, PhD, from the Dominick P. Purpura Department of Neuroscience.

[1] https://www.cell.com/neuron/fulltext/S0896-6273(23)00267-2
[2] https://einsteinmed.edu/
[3] https://neurosciencenews.com/molecular-memory-brain-23107/

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