Can’t remember something? Retry later in the day


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.

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.

Successful adaptation to aversive stimuli through the formation of associative memories is essential for the survival of most animals.

The physical correlate of these memories, the memory engram, represents long-lasting alterations of neurons and circuits that enable precise recall of stored information to modulate behavior [13]. 

Drosophila aversive olfactory conditioning has been successfully used in the past to unravel the molecular mechanisms underlying long-term associative memory [47].

The mushroom body (MB), the site of associative olfactory learning in insects, consists of 7 types (αβc, αβs, αβp, α’β’m, α’β’ap, γm, and γd) of Kenyon cells (KCs) that project into specific layers in the α/β, α’/β’, and γ MB lobes that represent functional domains dedicated to different aspects of memory acquisition, storage, and retrieval [819].

Olfactory information from approximately 50 antennal lobe glomeruli is provided in a stochastic manner via projection neurons (PNs) to approximately 2,000 KCs [2024]. KCs then transmit the information to only 34 MB output neurons (MBONs) in 15 anatomically defined lobular compartments [18,19].

Consistent with this anatomical architecture, MBONs are broadly tuned to odors, whereas olfactory sensory representation in KCs is sparse and thus well suited for memory association [2528]. The KC > MBON synaptic compartments are selectively innervated by dopaminergic neurons (DANs) that provide reinforcement signals of positive or negative valence during associative memory formation [18,2932].

Temporal pairing of an odor with an aversive stimulus results in KC activity that coincides with dopamine release and induces synaptic depression of the KC > MBON synapse in a compartment-specific manner [3335].

Because MBONs are known to direct approach or avoidance behavior [36,37], KC > MBON plasticity is thought to be sufficient to modulate behavior and store olfactory memories [38,39].

The recent complete synaptic reconstruction of the adult MB α lobe [40] and of the entire adult brain [41] in combination with genetic access to MBONs and DANs [18] provide a unique framework to unravel the cellular and circuit mechanisms underlying long-term memory (LTM).

Prior studies demonstrated that one subtype of KCs, the αβ surface neurons (500 cells), is essential for LTM recall [9], indicating that olfactory LTMs are stored within these neurons. The stochastic PN > KC synaptic connectivity and the sparse representation of olfactory information within a genetically identical subpopulation of KCs currently precludes the identification and characterization of the KCs encoding individual LTMs.

In mice, activity-dependent techniques based on the transcriptional activity of c-Fos enabled successful tagging and manipulation of engram cells [4244], and a similar approach has recently been described in Drosophila [45]. In addition to c-Fos, cellular consolidation of LTM requires protein synthesis and activity of the cAMP response element (CRE)-binding protein CREB in mice, Aplysia and Drosophila MBs [5,4556].

In this study, we generate a novel engram-tagging tool based on CRE-dependent transcriptional activity to specifically manipulate KCs encoding individual LTMs.

University of Tokyo
Media Contacts:
Satoshi Kida – University of Tokyo

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.


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