Forgetfulness might depend on time of day

Summary: Mouse study reveals a gene that influences memory recall at different times of the day. Researchers identified how the gene causes mice to be more forgetful just before they normally wake.

Source: University of Tokyo

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.

This shows a light bulb in a think bubble
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. The image is in the public domain.

“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.

About this neuroscience research article

Source:
University of Tokyo
Media Contacts:
Satoshi Kida – University of Tokyo
Image Source:
The image is in the public domain.

Original Research: Open access
“Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation”. 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.
Nature Communications doi:10.1038/s41467-019-13554-y.

Abstract

Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. However, functional roles of local brain circadian clocks in memory performance remains unclear. Here, we show that hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8–12, independently of retention delay, encoding time and Zeitgeber entrainment cue. This altered retrieval profile was associated with downregulation of hippocampal Dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Consistently, pharmacological activation of cAMP-signals or D1/5Rs rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation.

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