Multiple studies in animal models have shown that melatonin and its derivatives improve memory.
It is also known that the phosphorylation of certain memory-related proteins is required for the formation of both short- and long-term memories.
The molecular mechanisms underlying melatonin-induced memory enhancement, however, have remained a mystery. Medical researchers from Sophia University, Japan, have made significant findings that contribute significantly to the elucidation of the underlying mechanisms.
Regarding the premise of the study, lead author Professor Atsuhiko Chiba from the Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, said, “Our study aimed to investigate the effects of melatonin, ramelteon, and N1-acetyl-5-methoxyquinuramine on the relative phosphorylation levels of memory-related proteins in order to explore candidate signalling pathways associated with the receptor- and nonreceptor-mediated memory-enhancing effects of melatonin.”
In layman's terms, the research team, which included Dr Masahiro Sano (currently affiliated with Tohoku University) and Dr Hikaru Iwashita (currently affiliated with Kansai Medical University), investigated the effects of three compounds on memory formation: melatonin, a hormone secreted by the pineal gland in the brain; N1-acetyl-5-methoxyquinuramine (AMK), melatonin's biological Furthermore, they looked at "phosphorylation," which is the biochemical addition of phosphate groups to protein structures, in five key proteins involved in memory formation. Extracellular signal-regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), CaMKII, CaMKIV, and the cAMP-response element binding protein (CREB) were among them.
Initial studies on male mice clearly demonstrated that administration of melatonin, ramelteon, or AMK at a dose of 1 mg/kg aided in the formation of long-term memory. The researchers did not investigate the effects of the three compounds on female mice in order to avoid data variability caused by the reproductive cycles of female mammals.
Long-term memory formation in male mice was evaluated through a series of experiments based on the novel objection recognition task, or "NORT." In this study, laboratory mice were first acclimated to an experimental arena for 5 minutes per day for three days in a row. On the fourth day, mice were allowed to explore two identical objects in the experimental arena for 5 minutes (training phase). The male mice were tested twenty-four hours after the training phase was completed. One of the two familiar objects was replaced with a new or unfamiliar object during the testing phase.
A trained observer recorded the amount of time the mice spent exploring each object, which is a good measure of object recognition memory. It is well known that mice spend more time exploring novel objects and less time near familiar objects.
After sacrificing the rodents using standard protocols, the researchers investigated the effects of ramelteon and AMK on the phosphorylation of ERK, CaMKII, CaMKII, CaMKIV, and CREB in the male mouse brain.
Ramelteon/AMK treatment significantly increased phosphorylation of both ERK and CREB in the hippocampus, the mammalian brain's learning and memory centre. These drugs, however, significantly reduced CaMKII/ phosphorylation in the same brain region.
In the perirhinal cortex (PRC), which is also associated with memory functions, both ramelteon and AMK significantly increased ERK, and only ramelteon significantly increased CaMKIIβ phosphorylation. In the hippocampus/PRC, ramelteon/AMK did not affect the phosphorylation of CaMKIV.
Talking about the study’s results, Prof. Chiba concluded, “Our findings suggest that melatonin is involved in promoting the formation of long-term object recognition memory by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signalling pathways.”
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