Summary: Researchers shed new light on the molecular and genetic basis of long-term memory formation in the brain. A new study reveals a single stimulation to the synapses of hippocampal neurons triggered numerous cycles where the memory-coding Arc gene produced mRNA molecules that were then translated into synapse-strengthening Arc proteins. From the findings, researchers determined a novel feedback loop that helps explain how short-lived mRNA and proteins create long-term memories in the brain.
Source: Albert Einstein College of Medicine
Helping your mother make pancakes when you were three…riding your bike without training wheels…your first romantic kiss: How do we retain vivid memories of long-ago events?
As described in a paper published online on April 25 in Neuron, researchers at Albert Einstein College of Medicine have found the explanation.
“The ability to learn new information and store it for long periods is one of the brain’s most remarkable features,” said Robert H. Singer, Ph.D., a co-corresponding author of the paper.
“We’ve made a startling discovery in mice regarding the molecular basis for making those long-term memories.” Dr. Singer is professor of cell biology and in the Dominick P. Purpura Department of Neuroscience, chair emeritus of anatomy & structural biology, and director of the Program in RNA Biology at Einstein.
Some aspects of the cellular basis of memory were already known. They’re made by neurons (nerve cells) and stored in a brain region called the hippocampus. They form when repeated neural stimulation strengthens synapses—the connections between nerve cells.
Proteins are needed to stabilize the long-lasting synaptic connections required for long-term memories. The blueprints for those proteins are molecules of messenger RNA (mRNA) that, in turn, are transcribed (copied) from memory-associated genes.
“The paradox is that it takes a long time—several hours—to form a lasting memory, yet the mRNAs and proteins associated with making proteins disappear in less than an hour,” said Sulagna Das, Ph.D., first and co-corresponding author of the paper and research assistant professor of cell biology at Einstein. “How could that be?”
To answer that question, the research team developed a mouse model in which they fluorescently tagged all the molecules of mRNA that flow from Arc, a gene critically important for converting our activities and other experiences into long-term memories.
The researchers stimulated synapses in neurons from the mouse hippocampus and then—using high-resolution imaging techniques they developed—observed the results in individual nerve cells in real time.
To their amazement, they observed that a single stimulus to the neuron triggered numerous cycles in which the memory-coding gene Arc produced mRNA molecules that were then translated into synapse-strengthening Arc proteins.
“We saw that some of the protein molecules made from that initial synaptic stimulus go back to Arc and reactivate it, initiating another cycle of mRNA formation and protein production followed by several others,” said Dr. Singer.
“With each cycle, we saw more and more protein accumulating to form ‘hot spots’ at the synapse, which are where memories are cemented into place. We’d discovered a previously unknown feedback loop that explained how short-lived mRNAs and proteins can create long-lived memories,” said Dr. Das.
Consider what’s involved in memorizing a poem, suggested Dr. Singer: “To make a lasting memory requires that you read the poem repeatedly and each reading can be thought of as an intermittent stimulus that adds memory-building protein to the synapse.”
Dr. Das noted that faulty expression of the Arc gene has been implicated in memory difficulties in humans and is linked to neurological disorders including autism spectrum disorder and Alzheimer’s disease. “What we learn about Arc’s response to nerve-cell stimulation can provide insights into the causes of these health problems,” she noted.
The paper is titled “Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation.” Additional Einstein authors include Pablo Lituma, Ph.D., and Pablo Castillo, M.D., Ph.D., in the Dominick P. Purpura Department of Neuroscience.
About this memory research news
Original Research: Closed access.
“Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation” by Robert H. Singer et al. Neuron
Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation
- Reactivation of transcription drives cycling of the Arc gene in individual neurons
- Feedback from new proteins reinduces Arc transcription in the next cycle
- Arc mRNAs from later cycles localize to sites marked with previous Arc protein
- Repetitive translation in hotspots consolidates dendritic Arc in selective hubs
Activity-dependent expression of immediate early genes (IEGs) is critical for long-term synaptic remodeling and memory. It remains unknown how IEGs are maintained for memory despite rapid transcript and protein turnover. To address this conundrum, we monitored Arc, an IEG essential for memory consolidation.
Using a knockin mouse where endogenous Arc alleles were fluorescently tagged, we performed real-time imaging of Arc mRNA dynamics in individual neurons in cultures and brain tissue.
Unexpectedly, a single burst stimulation was sufficient to induce cycles of transcriptional reactivation in the same neuron. Subsequent transcription cycles required translation, whereby new Arc proteins engaged in autoregulatory positive feedback to reinduce transcription.
The ensuing Arc mRNAs preferentially localized at sites marked by previous Arc protein, assembling a “hotspot” of translation, and consolidating “hubs” of dendritic Arc.
These cycles of transcription-translation coupling sustain protein expression and provide a mechanism by which a short-lived event may support long-term memory.