Forgetfulness might depend on time of day

December 18, 2019

Can't remember something? Try waiting until later in the day. Researchers identified a gene in mice that seems to influence memory recall at different times of day and tracked how it causes mice to be more forgetful just before they normally wake up.

"We may have identified the first gene in mice specific to memory retrieval," said Professor Satoshi Kida from the University of Tokyo Department of Applied Biological Chemistry.

Every time you forget something, it could be because you didn't truly learn it -- like the name of the person you were just introduced to a minute ago; or it could be because you are not able to recall the information from where it is stored in your brain -- like the lyrics of your favorite song slipping your mind.

Many memory researchers study how new memories are made. The biology of forgetting is more complicated to study because of the difficulties of distinguishing between not knowing and not recalling.

"We designed a memory test that can differentiate between not learning versus knowing but not being able to remember," said Kida.

Researchers tested the memories of young adult male and female mice. In the "learning," or training, phase of the memory tests, researchers allowed mice to explore a new object for a few minutes.

Later, in the "recall" phase of the test, researchers observed how long the mice touched the object when it was reintroduced. Mice spend less time touching objects that they remember seeing previously. Researchers tested the mice's recall by reintroducing the same object at different times of 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 fluctuates between low levels just before waking up and high levels before going to sleep.

Mice trained just before they normally woke up and tested just after they normally went to sleep did recognize the object.

Mice trained at the same time -- just before they normally woke up -- but tested 24 hours later did not recognize the object.

Healthy mice and mice without BMAL1 had the same pattern of results, but the mice without BMAL1 were even more forgetful just before they normally woke up. Researchers saw the same results when they tested mice on recognizing an object or recognizing another mouse.

Something about the time of day just before they normally wake up, when BMAL1 levels are normally low, causes mice to not recall something they definitely learned and know.

According to Kida, the memory research community has previously suspected that the body's internal, or circadian, clock that is responsible for regulating sleep-wake cycles also affects learning and memory formation.

"Now we have evidence that the circadian clocks are regulating memory recall," said Kida.

Researchers have traced the role of BMAL1 in memory retrieval to a specific area of the brain called the hippocampus. Additionally, researchers connected normal BMAL1 to activation of dopamine receptors and modification of other small signaling molecules in the brain.

"If we can identify ways to boost memory retrieval through this BMAL1 pathway, then we can think about applications to human diseases of memory deficit, like dementia and Alzheimer's disease," said Kida.

However, the purpose of having memory recall abilities that naturally fluctuate depending on the time of day remains a mystery.

"We really want to know what is the evolutionary benefit of having naturally impaired memory recall at certain times of day," said Kida.

About the research

Mice are naturally nocturnal. When measured in units of time using zeitgeber, the environmental cue of light turning on, mice are usually asleep from Zeitgeber Time 1 to 12 and awake from Zeitgeber Time 12 to 24. The term "just before normally waking up" refers to Zeitgeber Time 10, while the term "just after normally going to sleep" refers to Zeitgeber Time 4.
-end-
Collaborators at the Tokyo University of Agriculture and the University of Toronto also contributed to this research.

Research Paper

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. 18 December 2019. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation. Nature Communications. DOI: 10.1038/s41467-019-13554-y

Related Links

Graduate School of Agricultural and Life Sciences: https://www.a.u-tokyo.ac.jp/english/

Department of Applied Biological Chemistry: http://www.bt.a.u-tokyo.ac.jp/english/introduction/

Research contact

Professor Satoshi Kida
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo
Tel: +81-(0)3-5841-5118
E-mail: akida@g.ecc.u-tokyo.ac.jp

Press Contact

Ms. Caitlin Devor
Division for Strategic Public Relations, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, JAPAN
Tel: +81-(0)3-5841-0876
Email: press-releases.adm@gs.mail.u-tokyo.ac.jp

About the University of Tokyo

The University of Tokyo is Japan's leading university and one of the world's top research universities. The vast research output of some 6,000 researchers is published in the world's top journals across the arts and sciences. Our vibrant student body of around 15,000 undergraduate and 15,000 graduate students includes over 4,000 international students. Find out more at http://www.u-tokyo.ac.jp/en/ or follow us on Twitter at @UTokyo_News_en.

Funders

Japan Society for the Promotion of Science, MEXT-Supported Program for the Strategic Research Foundation at Private Universities, Core Research for Evolutional Science and Technology (CREST), The Sumitomo Foundation, Takeda Science Foundation, The Naito Foundation, The Uehara Memorial Foundation, The Science Research Promotion Fund, The Promotion and Mutual Aid Corporation for Private Schools of Japan.

Grants

15H02488, 18H03944, 19H01047, 23300120, 20380078, 24650172, 26640014, 17K19464, 17H05962, 24116008, 24116001, 23115716, 17H06084, 17H05961, 17H05581, 18H05428, 18H05434, 19H04917, 18022038, 22022039, 24650172, 26640014, 17K19464, 15H02488, 18H03944, 19H01047, 23300120 and 20380078

University of Tokyo

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