Melatonin Regulates Daytime Learning Efficiency in Mice

by | Jun 7, 2021 | 2019, Brain Health, Melatonin

Written by Angeline A. De Leon, Staff Writer. Study findings suggest that melatonin does indeed play a role in shaping time-of-day-dependent learning efficiency in mammals. 

The mechanisms associated with learning and memory consolidation are known to be time-of-day dependent 1. In humans, as well as in fruit flies and zebrafish, mnemonic processes (memory acquisition, consolidation, retrieval) have been found to involve circadian rhythms, suggesting potential variation in learning and memory as a function of time of day 2-4. For example, learning efficiency in the hippocampus, a structure primarily associated with long-term memory (LTM) formation 5-7, has been noted as being dependent on the time-of-day 8-10. Animal research has revealed that melatonin, a hormone secreted by the pineal gland during nighttime, is critical for the circadian modulation of memory formation, with evidence suggesting that the disruption of melatonin production via pinealectomy can change the dynamics of daytime learning and nighttime memory formation 4. In mammals, however, the role of melatonin in temporal gating mechanisms associated with LTM formation and retrieval is less understood. Thus, in a 2019 paper 11 in the Journal of Pineal Research, investigators evaluated the influence of melatonin on the dynamics of hippocampal mnemonic processes and the role of circadian timing in learning efficiency.

Experimental procedures were carried out with C3H/He wildtype (WT) mice, three types of melatonin-receptor-knockout mice (MT1−/−, MT2−/−, MT1/2−/−), and melatonin-deficient C57BL/6 mice aged 8-12 weeks-old. Animals were made to perform an 8-arm radial maze task for five consecutive days to test for differences in spatial learning based on daytime vs. nighttime training. C57BL/6 mice were treated with melatonin (10 mg/100 ml water) starting three nights prior to the behavioral task and lasting throughout the duration of testing. Following anesthetization and decapitation of mice, immunohistochemical, immunoblotting, and real-time polymerase chain reaction (RT-PCR) analyses were performed in tissue samples harvested from the hippocampus.

Analyses from immunohistochemistry, immunoblotting, and RT-PCR revealed the presence of melatonin receptors on the membranes of hippocampal principal neurons, suggesting that melatonin functions at the level of expressed receptor proteins. More specifically, MT1 receptors were localized within the hippocampal formation of WT mice. PCR also showed that while relative protein expressions of time-of-day-dependent clock genes (PER1, PER2, CRY2, CLOCK, BMAL1) in the hippocampus of WT mice were associated with a significantly dynamic time-of-day-dependent pattern, clock gene protein levels in MT1/2−/− mice showed significant alterations in temporal dynamics, by comparison. For example, peak protein expression of CLOCK was found to be diminished in MT1/2−/− mice and phase-shifted from midnight to early day time, relative to WT. In regards to behavioral results, improved learning was observed for WT mice during the day vs. night (significantly fewer % errors, p ≤ 0.05), whereas MT1/2−/− mice demonstrated high error rates during both daytime and nighttime, suggesting no such improvement in daytime memory formation. Finally, treatment of C57BL/6 mice with melatonin at nighttime was found to significantly boost working memory performance during the daytime, compared to untreated mice (p < 0.05).

Experimental findings suggest that melatonin does indeed play a role in shaping time-of-day-dependent learning efficiency in mammals. Here, the presence of melatonin receptors was detected exclusively in hippocampal principal neurons, and deficiency in melatonin receptor signaling was linked to altered protein expression of time-of-day-dependent clock genes in the hippocampus (i.e., disruption of normal rhythm of clock gene expression). Behavioral results also suggested that the absence of normal melatonin receptors significantly impacted the temporal dynamics of hippocampal spatial learning, as MT1/2−/− mice failed to show the same improvement in daytime memory formation that WT mice demonstrated, instead showing equally poor performance during both day and night. Meanwhile, nighttime medication of C57BL/6 mice with melatonin produced substantial improvements in daytime learning. Taken together, results suggest that melatonin has a direct influence on signaling events in hippocampal neurocircuitry and that it modulates time-of-day-dependent learning and memory processes in mice. Findings warrant further verification in a human model of hippocampal mnemonic processes.

Source: Jilg A, Bechstein P, Saade A, et al. Melatonin modulates daytime-dependent synaptic plasticity and learning efficiency. J Pineal Res. 2019; 66(3): e12553. DOI: 10.1111/jpi.12553.

Click here to read the full text study.

Posted June 7, 2021.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

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