Long-term memory emerges from a sequence of molecular programs that sort, stabilize, and reinforce important experiences.
Understanding these timers may allow researchers to bypass damaged brain regions and preserve memories in degenerative conditions.
How the Brain Chooses What to Remember
Every day, the brain takes fleeting experiences, moments of creativity, and emotionally charged events and turns them into lasting memories that help shape who we are and how we make decisions. A major question has been how the brain chooses which pieces of information to preserve and how long each one should remain.
Recent research shows that long-term memories form through a series of molecular timing processes that unfold across different parts of the brain. Using a virtual reality-based behavioral system in mice, scientists found that specific molecular regulators guide memories along distinct paths, either strengthening them into more stable forms or allowing them to fade.
Multiple Brain Regions Orchestrate Long-Term Storage
The study, published today (November 16) in Nature, reveals that several brain regions work together to gradually transform new experiences into more permanent memories. Along the way, various checkpoints help determine which memories are important enough to be reinforced and preserved.
“This is a key revelation because it explains how we adjust the durability of memories,” says Priya Rajasethupathy, head of the Skoler Horbach Family Laboratory of Neural Dynamics and Cognition. “What we choose to remember is a continuously evolving process rather than a one-time flipping of a switch.”
Rethinking the Two-Region Memory Model
For many years, scientists concentrated primarily on two major players: the hippocampus, which supports short-term memory, and the cortex, thought to hold long-term memories. In this traditional view, long-term memories were believed to be controlled by molecular switches that were either on or off.
“Existing models of memory in the brain involved transistor-like memory molecules that act as on/off switches,” says Rajasethupathy.
This framework suggested that once a short-term memory was marked for long-term storage, it would remain fixed there. However, even as this model generated valuable insights, it became clear that it did not fully capture the complexity of memory stability or explain why some long-term memories last only weeks while others endure for a lifetime.
Using VR the scientists could control how many times mice experienced each memory, as well as which memories they experienced and when. Credit: Rajasethupathy lab/The Rockefeller University
The Thalamus’ Central Role in Stabilizing Memories
Then, in 2023, Rajasethupathy and colleagues published a paper that identified a brain pathway that links short and long-term memories. An important component of this is a region in the center of the brain called the thalamus, which not only helps select which memories should be remembered, but routes them to the cortex for long-term stabilization.
The findings set the stage for tackling 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 sorting process that promotes important memories to the cortex and demotes unimportant ones to be forgotten?
VR Experiments Reveal How Memory Persistence Forms
To answer these questions, the team developed a behavioral model using a virtual reality system where mice formed specific memories. “Andrea Terceros, a postdoc in my lab, created an elegant behavioral model [that] allowed us to break open this problem in a new way,” Rajasethupathy says. “By varying how often certain experiences were repeated, we were able to get the mice to remember some things better than others, and then look into the brain to see what mechanisms were correlated with memory persistence.”
But correlation was not enough. To demonstrate causality, co-lead Celine Chen developed a CRISPR screening platform to manipulate genes in the thalamus and cortex. With this tool, they could demonstrate that removing certain molecules impacted the duration of the memory. Strikingly, they also observed that each molecule affected that duration on different time-scales.
Molecular Timers Replace the Myth of a Single Switch
The results suggest that long-term memory is not maintained by a single molecular on/off switch, but by a cascade of gene-regulating programs that unfold over time and across brain regions like a series of molecular timers.
Initial timers turn on quickly and fade just as fast, allowing for rapid forgetting; later timers act more slowly but create more durable memories. This stepwise process allows the brain to promote important experiences for long-term storage, while others fade. In this study, the researchers used repetition as a proxy for importance, comparing memories of frequently repeated contexts to those encountered less often. The team identified three transcriptional regulators: Camta1 and Tcf4 in the thalamus, and Ash1l in the anterior cingulate cortex, which are not necessary for initially forming memories, but are crucial for maintaining them. Disrupting Camta1 and Tcf4 impaired functional connections between the thalamus and cortex, leading to memory loss.
Stepwise Stabilization
The model suggests that, after the basic memory is formed in the hippocampus, Camta1 and its targets ensure the initial persistence of the memory. With time, Tc4 and its targets are activated, providing cell adhesion and structural support to further maintain the memory. Finally, Ash1l recruits chromatin remodeling programs that make the memory more persistent.
“Unless you promote memories onto these timers, we believe you’re primed to forget it quickly,” Rajasethupathy says.
Interestingly, Ash1l belongs to a family of proteins called histone methyltransferases that retain memory in other biological systems as well. “In the immune system, these molecules help the body remember past infections; during development, those same molecules help cells remember that they’ve become a neuron or muscle and maintain that identity long-term,” Rajasethupathy says. “The brain may be repurposing these ubiquitous forms of cellular memory to support cognitive memories.”
Routing Memories Around Disease-Damaged Circuits
The findings may have implications for memory-related diseases. Rajasethupathy suspects that, by identifying the gene programs that preserve memory, researchers may eventually find ways to route memory through alternate circuits and around damaged parts of the brain in conditions such as 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, perhaps we can bypass the damaged region and let healthy parts of the brain take over,” she says.
Rajasethupathy’s next steps will focus on uncovering how the various molecular timers get turned on. And what sets their duration. Essentially, what tells the brain how important a memory is and how long it should last? Her lab is particularly focused on the role of the thalamus, which they have identified as a critical decision-making hub in this process.
Unraveling How Memories Live Beyond the Hippocampus
“We’re interested in understanding the life of a memory beyond its initial formation in the hippocampus,” Rajasethupathy says. “We think the thalamus, and its parallel streams of communication with cortex, are central in this process.”
Reference: “Thalamocortical transcriptional gates coordinate memory stabilization” by Andrea Terceros, Celine Chen, Yujin Harada, Tim Eilers, Millennium Gebremedhin, Pierre-Jacques Hamard, Richard Koche, Roshan Sharma and Priya Rajasethupathy, 26 November 2025, Nature.
DOI: 10.1038/s41586-025-09774-6
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