Scientists reveal how the brain decides which memories to retain

Scientists from Rockefeller University have shown that long-term memories are formed not by a single "switch" but by a whole cascade of molecular "timers" that work in stages in different brain areas.

The work is published in the journal Nature.

The classical model of memory has long been reduced to a duo:

• hippocampus - short-term memory,
• the cortex for long-term memory.

It was assumed that there are some "switch molecules": if a memory trace is "switched on" for long-term storage, it remains so for a long time. But this scheme did not explain why some memories live for weeks and others for a lifetime.

The new work shows that memory retention is regulated by sequential genetic programmes that are switched on and off at specific times and in different parts of the brain - like a series of timers with different durations.

To track the 'life' of a memory, the team created a behavioural model on mice in virtual reality:

• mice were placed in a VR environment with different contexts (environments),
• some episodes were repeated many times, others less often,
• so that memories of different "importance" and persistence were formed.

The researchers then

• monitored the activity of different brain areas,
• used CRISPR screening to switch off genes in the thalamus and anterior cingulate cortex and see how this affected memory duration.

The key finding: some molecules are not necessary for memory formation but are critical for memory retention.

The scientists identified three important regulators:

• Camta1 and Tcf4 - in the thalamus;
• Ash1l in the anterior cingulate cortex.

According to the model:

1. A memory trace is first formed in the hippocampus.
2. Camta1 helps this trace to "hold on" in the first stages.
3. Later, Tcf4 is activated, maintaining structural connections and stabilising the memory track.
4. Ash1l then triggers chromatin rearrangement programmes - and the memory becomes more stable and long-term.

If a memory fails to "advance" further along this chain of timers, it is likely to be rapidly erased.

Disruption of Camta1 and Tcf4 disrupted the connections between the thalamus and cortex and resulted in the loss of an already formed memory.

Interestingly, Ash1l is related to a family of histone methyltransferases that are involved in "cellular memory" and other systems:

• in immunity - to remember infections,
• in development, so that the cell remembers that it's a neuron or a muscle cell, for example.

The brain, in fact, uses the universal mechanisms of "cellular memory" to support cognitive memory.

The new model of memory involves:

• the decision "what to store and for how long" is a dynamic process, not a one-off choice;
• the thalamus plays the role of a decision-making centre that decides which memories to "push" further into the cortex for consolidation;
• memory persistence is the result of multiple molecular programmes deployed over time.

The authors suggest that understanding these pathways could be useful in:

• diseases like Alzheimer's disease,
• other memory disorders and cognitive decline.

If it is known which "second and third" nodes are involved in memory consolidation, it may be possible in the future to bypass damaged regions and activate alternative pathways to store memories.