A team of scientists in Japan has identified a gene that may influence how good memory recall is at different times of day. The experiments in mice indicated that the gene, BMAL1, causes the animals to be more forgetful just before they normally wake up. “We may have identified the first gene in mice specific to memory retrieval,” said Satoshi Kida, PhD, at the University of Tokyo department of applied biological chemistry. “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.” Kida is corresponding author of the researchers’ published paper in Nature Communications, which is titled, “Hippocampal clock regulates memory retrieval via dopamine and PKA-induced GluA1 phosphorylation.”

Circadian rhythms regulate many physiological, biological, and behavioral processes in mammals, the authors explained. This even extends to memory. “Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening.” In fact, while studies as far back as 1885 have demonstrated that time-of-day influences memory, “the underlying mechanisms haven’t been understood.”

Molecular mechanisms mediated by BMAL1 and CLOCK in the suprachiasmatic nuclei (SCN) region of the anterior hypothalamus are believed to play a key role in the control of circadian rhythms. “Time-of-day oscillations in the transcriptional activity of clock genes (including BMAL1 and CLOCK) in the central pacemaker, the SCN, are essential for generating circadian transcriptional rhythm,” the scientists continued.

However, they pointed out, evidence also suggests that molecular clocks in other parts of the brain and in peripheral tissues may also play a role in autonomous circadian regulation of tissue-specific functions. “Interestingly, in addition to the SCN, BMAL1/CLOCK-mediated transcriptional rhythms are observed in other parts of the brain, as well as peripheral tissues, including muscle and liver … Importantly, there is increasing evidence that molecular clocks in these extra-SCN regions exert autonomous circadian regulation of tissue-specific function.”

When we forget something it could be simply because we hadn’t really learnt it—perhaps the name of the person of someone we were introduced to a minute ago—or it could be because we can’t recall the information from where it is stored in the brain. Say, not being able to recall the lyrics of a favorite song. This difference means that the biology of forgetting is more complicated to study than the biology of how memories are made, because of the difficulties of distinguishing between not knowing and not recalling.

Kida and colleagues devised a test to assess the memories of young adult male and female mice, and in particular the role of the molecular clock in the hippocampus in memory processing. “We designed a memory test that can differentiate between not learning versus knowing but not being able to remember,” Kida explained. 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.

The experiments were designed to determine whether mice showed time-of-day changes in memory retrieval performance, and included hippocampus-dependent object recognition and social recognition tasks. In the “learning,” or training, phase of the memory tests, the test mouse was allowed to explore a new object for a few minutes. Later, in the “recall” phase of the test, researchers observed for how long the test mice interacted with the same object when reintroduced. Mice spend less time touching objects that they remember seeing previously. Researchers were able to test recall in the mice by reintroducing objects at different times of day.

They did the same experiments with healthy mice and with mice lacking the BMAL1 protein, which regulates the expression of many other genes. BMAL1 normally fluctuates between low levels just before waking up and high levels before going to sleep. The experiments indicated that healthy mice trained just before they normally woke up and tested just after they normally went to sleep did recognize the object. However, mice trained at the same time—just before they normally woke up—but tested 24 hours later did not recognize the object. Something about the time of day just before the animals would normally wake up, when BMAL1 levels are normally low, hampered the animals’ ability to recall something they definitely learned and know. And while the mice engineered to lack BMAL1 demonstrated the same pattern of results when tested in the same way, they were even more forgetful just before they normally woke up. Researchers saw the same results when they tested the ability of mice to recognize another mouse, rather than an object.

“Here we show that fluctuations in forebrain (and in particular hippocampal) levels of the key clock transcription factor regulate retrieval,” the authors concluded. “Strikingly, our findings suggest that the rates of BMAL1-mediated transcription determine retrieval success. When BMAL1 activity is upregulated (e.g., at ZT4), retrieval is enhanced, whereas when BMAL1 activity are downregulated (e.g., ZT10) retrieval is impaired. These data identify a role for BMAL1 in memory processing and indicate that time-of-day effects on memory retrieval are mediated by local, hippocampal cell-autonomous oscillators.”

“Now we have evidence that the circadian clocks are regulating memory recall,” said Kida. While the role of BMAL1 in memory retrieval has been mapped to the hippocampus, researchers have also connected normal BMAL1 to activation of dopamine receptors and the modification of other small signaling molecules in the brain.

What 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.

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