Researchers discover that time of day influences memory recall, mediated by the hippocampal circadian clock in mice.
Important mammalian processes such as metabolism, sleep patterns, heart rate, blood pressure, and body temperature are regulated by the body’s internal or 24-hour cycle based circadian clock. In humans, a master biological clock in a tiny region of the hypothalamus called the suprachiasmatic nucleus (SCN) keeps other independent, secondary biological clocks such as the hippocampal clock in sync. Circadian rhythm of gene expression is generated when proteins BMAL1 and CLOCK work together to turn genes on and off influenced by the time of day. In mice that are nocturnal, BMAL1 levels are endogenously lower just before waking up (when it is almost dark) and endogenously higher just before bed (when it is light). In a recent article published in Nature Communications, researchers discover that fluctuations in hippocampal BMAL1 activity regulates memory recall.
Researchers designed a memory test in 2 groups of mice: healthy mice and mice without BMAL1. The memory test consisted of 2 phases. In the “learning” or memory encoding phase, mice were allowed to explore either a new juvenile mouse or a new object for a few minutes. In the “recall” phase, researchers observed how long it took the mice to recognize the same mouse or object later at different times of the day. Poor memory recall can be the result of not truly learning the information or not being able to recall the information from where it is stored in the brain. To distinguish between not truly learning and not being able to recall, researchers also looked at memory recall at different times of the day of mice who received a longer or stronger “learning” phase.
Researchers found that the time-of-day of the “learning phase” did not influence memory recall for both healthy mice and mice without BMAL1. Instead, they discovered that time-of-day influenced memory recall. Healthy mice showed impaired memory recall just before waking up. In contrast, memory recall just before bed was not impaired for healthy mice. For mice without BMAL1, they found that memory recall was impaired at all times and that mice who received a longer “learning” phase demonstrated restored memory recall just before bed but not before waking up. Together these results suggest that when BMAL1 activity is upregulated, occurring endogenously just before bed, memory recall is enhanced. However, when BMAL1 activity is downregulated, occurring endogenously just before waking up, memory recall is impaired. Similar results were observed when researchers tested mice who were exposed to constant darkness indicating that memory recall does not depend on external time of day cues but endogenous cues. The researchers note that future studies are needed to confirm results.
Although researchers do not know the purpose of fluctuating memory recall abilities based on time of day, they have further identified BMAL1 activity to include dopamine receptor activation and PKA (a small molecule)-induced phosphorylation (adding a phosphate group). The next step is to identify ways that the BMAL1 signaling pathway can be modified to boost memory recall which could have an application in helping memory recall in individuals with dementia or Alzheimer’s disease.
Written by Maria-Elena Bernal B.Sc. (Hons)
Hasegawa, S., Fukushima, H., Hosoda, H. et al. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation. Nat Commun 10, 5766 (2019) doi:10.1038/s41467-019-13554-y
UTokyo_News_en. (n.d.). Forgetfulness might depend on time of day. Retrieved from https://www.eurekalert.org/pub_releases/2019-12/uot-fmd121519.php.
Circadian Rhythms and the Brain. (n.d.). Retrieved from https://neuro.hms.harvard.edu/harvard-mahoney-neuroscience-institute/brain-newsletter/and-brain-series/circadian-rhythms-and-brain.
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