Summary: New research shows that long-term memory is not stored by a single molecular switch, but by a sequence of timed genetic programs that develop in different regions of the brain. Using a virtual reality learning model in mice, scientists found that experiences are promoted or degraded through multiple biological “durability gates.”
Early molecular timers allow rapid forgetting, while later ones stabilize long-term memories. This cascading system explains why some memories fade quickly while others last a lifetime.
Key facts
Timed memory control: Long-term memory is regulated by multiple sequential molecular programs, not a single switch. Regional coordination: Memory persistence depends on coordinated activity between the thalamus and cortex. Durability at the genetic level: Specific genetic regulators determine whether memories weaken or stabilize over time.
Source: Rockefeller University
Every day, our brain transforms quick impressions, flashes of inspiration, and painful moments into lasting memories that sustain our sense of identity and inform how we navigate the world.
But how does the brain decide which bits of information are worth keeping and how long to keep them?
Now, new research shows that long-term memory is formed by a cascade of molecular timers that unfold in brain regions. Using a virtual reality-based behavioral model in mice, scientists discovered that long-term memory is orchestrated by key regulators that promote memories into progressively longer-lasting forms or degrade them until they are forgotten.
The findings, published in Nature, highlight the role of multiple brain regions in gradually reorganizing memories into more durable forms, with gates along the way to assess salience and promote durability.
“This is a key revelation because it explains how we fine-tune the durability of memories,” says Priya Rajasethupathy, director of the Skoler Horbach Family Cognition and Neural Dynamics Laboratory. “What we choose to remember is a continually evolving process rather than flipping a switch once.”
The persistence of memory
For decades, memory research focused on two brain regions: the hippocampus, home of short-term memory, and the cortex, thought to house long-term memories. Scientists imagined that the latter are locked behind biological on-off switches.
“Existing models of memory in the brain involved transistor-like memory molecules that act as on-off switches,” says Rajasethupathy.
In other words, in this model, if a short-term memory were labeled for long-term storage, it would remain that way indefinitely. But even as research in this direction led to numerous insights, researchers realized that this model was ultimately too simple; for example, it did not explain why some long-term memories last weeks while others last a lifetime.
Then, in 2023, Rajasethupathy and his colleagues published a paper that identified a brain pathway that links short- and long-term memories. An important component is a region in the center of the brain called the thalamus, which not only helps select which memories should be remembered, but also directs them to the cortex for long-term stabilization.
The findings lay the groundwork for addressing some of the most fundamental questions in the field of memory research: What happens to memories beyond short-term storage in the hippocampus, and what molecular mechanisms are behind the classification process that promotes important memories in the cortex and degrades the forgetting of unimportant ones?
To answer these questions, the team developed a behavioral model using a virtual reality system in which mice formed specific memories.
“Andrea Terceros, a postdoc in my lab, created an elegant behavioral model that allowed us to solve this problem in a new way,” says Rajasethupathy.
“By varying the frequency with which certain experiences were repeated, we were able to get mice to remember some things better than others and then looked at the brain to see what mechanisms correlated with memory persistence.”
But the correlation was not enough. To demonstrate causality, co-director Celine Chen developed a CRISPR screening platform to manipulate genes in the thalamus and cortex. With this tool, they were able to show that the elimination of certain molecules affected the duration of memory. Surprisingly, they also observed that each molecule affected that duration on different time scales.
timed entry
The results suggest that long-term memory is not maintained by a single molecular on/off switch, but by a cascade of gene regulatory programs that unfold over time and across brain regions like a series of molecular timers.
Initial timers activate quickly and fade out just as quickly, allowing for quick forgetting; Later timers act more slowly but create longer lasting memories. This gradual process allows the brain to promote important experiences for long-term storage while others fade away. In this study, the researchers used repetition as an indicator of importance, comparing memories from frequently repeated contexts with those encountered less frequently.
The team identified three transcriptional regulators: Camta1 and Tcf4 in the thalamus, and Ash1l in the anterior cingulate cortex, which are not necessary for the initial formation of memories, but are crucial for maintaining them. Disruption of Camta1 and Tcf4 affected functional connections between the thalamus and cortex, leading to memory loss.
The model suggests that, once basic memory is formed in the hippocampus, Camta1 and its targets ensure the initial persistence of the memory. Over time, Tc4 and its targets are activated providing cell adhesion and structural support to further maintain memory. Finally, Ash1l recruits chromatin remodeling programs that make memory more persistent.
“Unless you transfer memories to these timers, we think you’re primed to forget them quickly,” Rajasethupathy says.
Interestingly, Ash1l belongs to a family of proteins called histone methyltransferases that also retain memory in other biological systems.
“In the immune system, these molecules help the body remember past infections; during development, those same molecules help cells remember that they have become a neuron or a muscle and maintain that identity long-term,” Rajasethupathy says.
“The brain may be reusing these ubiquitous forms of cellular memory to support cognitive memories.”
The findings may have implications for memory-related diseases. Rajasethupathy suspects that by identifying the genetic programs that preserve memory, researchers could eventually find ways to route memory through alternative circuits and around damaged parts of the brain in conditions like Alzheimer’s.
“If we know the second and third areas that are important for memory consolidation, and we have neurons dying in the first area, maybe we can avoid the damaged region and let healthy parts of the brain take over,” he says.
Rajasethupathy’s next steps will focus on discovering how different molecular timers are activated. And what marks its duration. Essentially, what tells the brain how important a memory is and how long it should last? Their lab particularly focuses on the role of the thalamus, which they have identified as a critical decision-making center in this process.
“We are interested in understanding the life of a memory beyond its initial formation in the hippocampus,” says Rajasethupathy. “We believe that the thalamus and its parallel streams of communication with the cerebral cortex are fundamental in this process.”
Key questions answered:
A: It uses a series of stepped molecular “timers” that gradually stabilize or erase memories.
A: It develops through multiple time-based genetic programs in various regions of the brain.
A: Yes: specific genetic regulators actively determine how long a memory persists.
Editorial notes:
This article was edited by a Neuroscience News editor. Magazine article reviewed in its entirety. Additional context added by our staff.
About this research news in memory and neuroscience
Author: Katherine Fenz
Source: Rockefeller University
Contact: Katherine Fenz – Rockefeller University
Image: Image is credited to Neuroscience News.
Original Research: Closed access.
“Thalamocortical transcriptional gates coordinate memory stabilization” by Priya Rajasethupathy et al. Nature
Abstract
Thalamocortical transcriptional gates coordinate memory stabilization
The molecular mechanisms that allow memories to persist for long periods of time, from days to weeks and months, are still poorly understood.
Here, to develop insights into this process, we created a behavioral task in which mice formed multiple memories but only consolidated some, while forgetting others, over the course of weeks.
We then monitored circuit-specific molecular programs that diverged between consolidated and forgotten memories. We identified multiple distinct waves of transcription, i.e., cellular macrostates, in the thalamocortical circuitry that defined memory persistence.
Of note, a small set of transcriptional regulators orchestrated broad molecular programs that enabled entry into these macrostates.
Targeted CRISPR knockdown studies revealed that although these transcriptional regulators had no effects on memory formation, they had prominent, causal, and strikingly time-dependent roles in memory stabilization.
In particular, the calmodulin-dependent transcription factor CAMTA1 was required for initial memory maintenance for days, while the transcription factor TCF4 and the histone methyltransferase ASH1L were later required for memory maintenance for weeks.
These results identify a critical thalamocortical transcriptional cascade CAMTA1 – TCF4 – ASH1L that is required for memory stabilization and present a model in which sequential recruitment of circuit-specific transcriptional programs enables memory maintenance over progressively longer time scales.
