Long-term memory is not an ‘on/off’ switch, it’s formed by cascade of molecular timers: Study

Brain researchers long knew that the model for studying memory oversimplified the complex processes that the brain uses to decide what to keep and for how long. A new study demonstrated a cascade of molecular timers unfolding across the brain regions to store long-term memory. For decades, memory research has focused on the hippocampus and the cortex, which are thought to be responsible for storing short-term and long-term memories.

However, this model, although it did lead researchers to valuable insights, did not account for the whole picture. Why do some long-term memories last weeks while others last a lifetime? The latest research from Priya Rajasethupathy, head of the Skoler Horbach Family Laboratory of Neural Dynamics and Cognition, builds upon previous studies, notably in 2023, that identified a pathway between short and long-term memories: the thalamus, which not only selects which memories to remember but then directs them to the cortex for long-term storage.

A press release continues that this research allowed these scientists to continue penetrating the intricate set of processes behind memory and retention. What happens to memories beyond short-term storage in the hippocampus? What molecular mechanisms are behind the sorting process that promotes important memories to the cortex and demotes unimportant ones to be forgotten? Researchers went into the lab after developing a behavioral model using a virtual reality system where mice formed specific memories.

Turns out that long-term memory isn’t exactly a switch, but a rather intriguing series of “molecular timers.” Not an on/off switch Existing models of memory in the brain involved transistor-like memory molecules that act as on/off switches, says Rajasethupathy in the press release. At the forefront of this research, the latest development in their pursuit to evolve this understanding of how the brain remembers enabled the team to “crack open this problem in a new way.” They were able to influence how the mice remembered by varying how often certain experiences they were having were repeated.

Some mice retained memories better than others. Then, they looked into the brain to investigate which mechanisms correlated with memory persistence. Correlation was not enough, however.

They needed to factor in causality. Co-lead on the study, 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,” as stated in a press release.

Long-term memory is an orchestration The results then suggest that there isn’t a single on and off switch to store memories long-term, but rather there’s a “cascade of gene-regulating programs that unfold over time and across the brain like a series of molecular timers.” “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 concludes in a press release.

The findings stand to impact memory-related brain diseases. Read the study in Nature.