Recent animal study investigates how melatonin may impact long-term memory formation


Melatonin may impact long-term memory by modulating the phosphorylation levels of memory-related proteins in both receptor-mediated and nonreceptor-mediated signaling pathways.

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A recent study1 found that melatonin and its derivatives may have a beneficial impact on long-term memory. Researchers from Sophia University in Japan used a murine model to investigate how melatonin, ramelteon which is a drug that binds and activates the melatonin receptor, and a brain melatonin metabolite called N1-acetyl-5-methoxyquinuramine (AMK) impact “phosphorylation levels of memory-related proteins in order to explore candidate signaling pathways associated with the receptor-mediated and nonreceptor-mediated memory-enhancing effects of melatonin.”

“Phosphorylation” is the biochemical addition of phosphate groups to protein structures, explains a press release. This was measured in five key proteins involving memory formation, namely: extracellular signal-regulated kinase (ERK), calcium/calmodulin-dependent kinase IIα (CaMKIIα), CaMKIIβ, CaMKIV, and the cAMP-response element binding protein (CREB).

First, researchers assessed long-term memory formation in male mice through a series of experiments based on the novel object recognition task (NORT). Mice are known to spend more time exploring objects that are novel than those that are familiar. Therefore, the researchers placed two identical objects in front of the mice which they were allowed to explore for five minutes. After 24 hours, one of the now familiar objects was placed in front of the mice with a new unfamiliar object. Researchers then measured the time spent by mice exploring each object to measure object recognition memory. Melatonin, ramelteon, and AMK all promoted long-term memory formation according to these tests.

Researchers then investigated the phosphorylation of the five memory formation proteins in the brains of mice that were given ramelteon and AMK. They observed that in the hippocampus, the learning and memory center of the mammalian brain, both ramelteon and AMK significantly increased the phosphorylation of ERK and CREB, but significantly decreased CaMKIIα/β. ERK phosphorylation was also increase in the perirhinal cortex by both treatments, but only ramelteon increased CaMKIIα/β phosphorylation. Neither treatment effected the phosphorylation of CaMKIV in the hippocampus.

“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 signaling pathways,” said Professor Atsuhiko Chiba, the study’s lead author, and faculty member from the Department of Materials and Life Sciences at Sophia University in a press release.

The implication of this study, say the researchers, is the development of new drugs that improve memory function is people suffering from age-related memory impairment.


  1. Sano, M.; Iwashita, H.; Suzuki, C.; Kawaguchi, M.; Chiba, A. Effects of Melatonin on Phosphorylation of Memory-Related Proteins in the Hippocampus and the Perirhinal Cortex in Male Mice. NeuroReport, 2023, 34(9): 457-462. DOI: 10.1097/WNR.0000000000001911
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