How the brain decides what to remember

Every day, our brains transform quick impressions, flashes of inspiration, and painful moments into enduring memories that underpin our sense of self and inform how we navigate the world. But how does the brain decide which bits of information are worth keeping—and how long to hold on?

Now, new research demonstrates that long-term memory is formed by a cascade of molecular timers unfolding across brain regions. With a virtual reality-based behavioral model in mice, the scientists discovered that long-term memory is orchestrated by key regulators that either promote memories into progressively more lasting forms or demote them until they are forgotten.

The findings, published in Nature, highlight the roles of multiple brain regions in gradually reorganizing memories into more enduring forms, with gates along the way to assess salience and promote durability.

"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.”

The persistence of memory

For decades, memory research focused on two brain regions: the hippocampus, home of short-term memory, and the cortex, which was thought to house long-term memories. The latter, scientists imagined, lie gated behind biological on-and-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 was tagged for long-term storage, it would remain so indefinitely. But, even as investigations in this vein led to numerous insights, researchers understood that this model was ultimately too simple—for instance, it didn't account for why some long-term memories last weeks while others last a lifetime.

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 which 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 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?

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 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.

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-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.

The model suggests that, after the basic memory is formed in the hippocampus, Camta1 and its targets ensures 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."

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.

“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.”

 

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