Don't you remember something? Try to wait later in the day. Researchers have identified a gene in mice that seems to influence memory recall at different times of the day and have tracked how it makes mice more forgetful just before they wake up normally.
"We may have identified the first gene in mice specific for memory recovery," said Professor Satoshi Kida of the Department of Applied Biological Chemistry at the University of Tokyo.
Whenever you forget something, it may be because you haven't really learned it - like the name of the person you just discovered a minute ago; or it could be due to the fact that you cannot remember the information from where it is stored in your brain - like the lyrics of your favorite song that you miss.
Many memory researchers are studying how new memories are created. The biology of forgetting is more complicated to study because of the difficulties in distinguishing between not knowing and not remembering.
"We have designed a memory test that can make the difference between not learning and not knowing but not remembering," said Kida.
Researchers tested the memory of young adult male and female mice. In the “learning” or training phase of memory tests, the researchers allowed the mice to explore a new object for a few minutes.
Later, in the "recall" phase of the test, the researchers observed how long the mice touched the object when it was reintroduced. Mice spend less time touching objects they remember having seen before. The researchers tested the recall of the mice by reintroducing the same object at different times of the day.
They did the same experiments with healthy mice and mice without BMAL1, a protein that regulates the expression of many other genes. BMAL1 normally oscillates between low levels just before waking up and high levels before falling asleep.
Mice trained just before normal waking and tested just after falling asleep recognized the object.
The mice trained at the same time - just before their normal awakening - but tested 24 hours later did not recognize the object.
Healthy mice and mice without BMAL1 had the same pattern of results, but mice without BMAL1 were even more forgetful just before waking up normally. The researchers saw the same results when they tested mice on the recognition of an object or the recognition of another mouse.
Something about the time of day right before they wake up normally, when BMAL1 levels are normally low, makes the mice not remember something they have definitely learned and know.
According to Kida, the memory research community previously suspected that the body's internal or circadian clock, which is responsible for regulating sleep-wake cycles, also affects learning and memory formation.
"We now have evidence that circadian clocks regulate memory recall," said Kida.
The researchers traced the role of BMAL1 in recovering memory to a specific area of the brain called the hippocampus. In addition, the researchers linked the normal BMAL1 to the activation of dopamine receptors and the modification of other small signaling molecules in the brain.
"If we can identify ways to stimulate memory recovery through this BMAL1 pathway, then we can think of applications for human memory deficiency diseases, such as dementia and Alzheimer's disease," said Kida.
However, the goal of having memory recall capabilities that naturally fluctuate with the time of day remains a mystery.
"We really want to know what is the evolutionary advantage of having naturally impaired memory at certain times of the day," said Kida.
Mice are naturally nocturnal. When measured in time units using zeitgeber, the environmental signal of light that turns on, mice are usually asleep from Zeitgeber Time 1 to 12 and awake from Zeitgeber Time 12 to 24. The term " just before waking up normally "refers to Zeitgeber Time 10, while the term" immediately after falling asleep normally "refers to Zeitgeber Time 4.
Collaborators from Tokyo University of Agriculture and the University of Toronto also contributed to this research.
Shunsuke Hasegawa, Hotaka Fukushima, Hiroshi Hosoda, Tatsurou Serita, Rie Ishikawa, Tomohiro Rokukawa, Ryouka Kawahara-Miki, Yue Zhang, Miho Ohta, Shintaro Okada, Toshiyuki Tanimizu, Sheena A. Josselyn, Paul W. Frankland, Satoshi Kida. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-13554-y