Why some memories last a lifetime while others fade fast

Recent findings show that long-term memories form through a sequence of molecular timing mechanisms that activate across different parts of the brain. Using a virtual reality behavioral system in mice, scientists identified regulatory factors that help move memories into increasingly stable states or allow them to fade entirely.

A study published in Nature highlights how several brain regions work together to reorganize memories over time, with checkpoints that help assess how significant each memory is and how durable it should be.

"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."

Moving Beyond the Classic Memory Model

For many years, researchers focused on two primary memory centers: the hippocampus, which supports short-term memory, and the cortex, which was believed to store long-term memories. These long-term memories were thought to sit 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.

This older view suggested that once a memory was marked for long-term storage, it would persist indefinitely. Although this framework provided useful insights, it did not explain why some long-term memories last for weeks while others remain vivid for decades.

A Key Pathway Linking Short and Long-Term Memory

In 2023, Rajasethupathy and colleagues described a brain circuit that connects short-term and long-term memory systems. A central element of this pathway is the thalamus, which helps determine which memories should be kept and directs them to the cortex for long-term stabilization.

These discoveries opened the door to deeper questions: What happens to memories once they leave the hippocampus, and what molecular processes decide whether a memory becomes lasting or disappears?

Virtual Reality Experiments Reveal Memory Persistence

To investigate these mechanisms, the team built a virtual reality setup that allowed mice to form 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."

Correlation alone could not answer the key questions, so co-lead Celine Chen created a CRISPR-based screening platform to alter gene activity in the thalamus and cortex. This approach showed that removing certain molecules changed how long memories lasted, and each molecule operated on its own timescale.

Timed Programs Guide Memory Stability

The results indicate that long-term memory relies not on a single on/off switch, but on a sequence of gene-regulating programs that unfold like molecular timers across the brain.

Early timers activate quickly but fade fast, allowing memories to disappear. Later timers turn on more gradually, giving important experiences the structural support needed to persist. In this study, repetition served as a stand-in for importance, letting researchers compare frequently repeated contexts with those seen only occasionally.

The team identified three transcriptional regulators essential for maintaining memories: Camta1 and Tcf4 in the thalamus, and Ash1l in the anterior cingulate cortex. These molecules are not required to form the initial memory but are crucial for preserving it. Disrupting Camta1 and Tcf4 weakened connections between the thalamus and cortex and caused memory loss.

According to the model, memory formation begins in the hippocampus. Camta1 and its downstream targets help keep that early memory intact. Over time, Tcf4 and its targets activate to strengthen cell adhesion and structural support. Finally, Ash1l promotes chromatin remodeling programs that reinforce memory stability.

"Unless you promote memories onto these timers, we believe you're primed to forget it quickly," Rajasethupathy says.

Shared Memory Mechanisms Across Biology

Ash1l is part of a protein family known as histone methyltransferases, which help maintain memory-like functions in other systems. "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."

These discoveries may eventually help researchers address memory-related diseases. Rajasethupathy suggests that, by understanding the gene programs that preserve memory, scientists may be able to redirect memory pathways around damaged brain regions 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.

Next Steps: Decoding the Memory Timer System

Rajasethupathy's team now aims to uncover how these molecular timers are activated and what determines their duration. This includes investigating how the brain evaluates the importance of a memory and decides how long it should last. Their work continues to point toward the thalamus as a central hub in this decision-making 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."