An interesting new paper describes the discovery of a gene in mice that affects the degree of memory recall at various times of day. They found that this gene makes mice most forgetful at the time immediately before they wake. Calling this possibly “the first gene in mice specific to memory retrieval”, the researchers think they may have begun to discover what makes humans forgetful as well. The research titled, 'Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation', is published in the journal Nature Communications.
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Forgetting is a word that means nothing much to most of us. However, in neuropsychological terms, it implies a lot. Forgetfulness could mean that you don’t remember something because you never actually learned it, in the sense that it never really entered your memory. Many trivial pieces of information are in this category. For instance, you might ‘forget’ the name of a new person you just met a short while ago.
Another category of forgetfulness is failing to retrieve the information required from its location in your brain – like something you know very well but can’t recall.
Learning and forgetting – or never knowing at all?
The study of memory formation and retrieval is a fascinating subject and has been the focus of much research so far. The process of forming a memory is a complicated one. But far more complex is the study of the science behind forgetting – because the first distinction to be made is between whether the person actually knew the matter in question and then failed to retrieve it, or never knew it at all.
The researchers in the current study set up a new kind of memory test that would be able to distinguish the two kinds of ‘forgetting’. They looked at the memories of young adult mice, both male and female. In the first phase, called the ‘learning’ phase, they let the mice discover a new object for several minutes. The next phase was the ‘recall’ phase, in which the researchers measured how long was the period in which the mice touched the object the next time they saw it. It is already known that mice don’t spend as much time on touching objects which are familiar to them.
The researchers looked at how long mice spent touching the object when it was presented at different times of day (not to the same mouse, of course). They also repeated the experiment with mice lacking the BMALI 1 gene, which codes for a protein that controls how many other genes are expressed. This protein is found to be present at widely varying levels depending on the time of day. For instance, its level is very low just before the animal normally wakes but is high at the time it goes to sleep.
To test the function of this gene in memory formation and retrieval, the researchers presented the new object to the mice just before normal waking time. They then tested its recall just before they normally went to sleep, and 24 hours later, in two groups of mice.
The current study found that recall of the new object was high in the first group, but poor in the second. This pattern was similar in both healthy mice and BMAL 1-deficient mice, but the forgetfulness was intensified in the latter. They repeated the experiment with another object, and then with another mouse – with the same results.
They came to the conclusion that though the mice did learn about the object when it was presented to them, as shown by the first mouse group, they were extremely forgetful around the time just before normal waking time. This is the time associated with very low BMAL 1 levels. Thus the time of day does affect memory retrieval, and this gene could play a role in this forgetfulness.
Circadian rhythms and memory recall
Earlier studies have shown that the body’s natural rhythms that play an important role in controlling the sleep-wake cycles are also involved closely in the tasks of learning and of forming new memories. Researcher Satoshi Kida says the current study provides evidence that circadian rhythms also regulate memory recall.
The BMAL 1 gene is implicated in memory retrieval in a particular brain area called the hippocampus. In its normal form, the gene has been found to activate dopamine receptors and to modify other small molecules that play a signaling function in the brain.
Kida thinks that knowing how the BMAL 1 gene works to retrieve memory can help to develop new therapies to reverse memory loss in human medical conditions like dementia and Alzheimer’s disease. A fundamental mystery remains to be solved, however: how does it help to have fluctuating memory recall abilities with the passage of time over one day? How would having poor recall at certain times of day help the animal? This is one area about which Kida and his colleagues are intensely curious.
Hasegawa, S., Fukushima, H., Hosoda, H. et al. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation. Nat Commun 10, 5766 (2019) doi:10.1038/s41467-019-13554-y, https://www.nature.com/articles/s41467-019-13554-y