Melatonin's role in memory: Study in mice offers fresh insights

• Memory formation is the focus of ongoing research, with questions remaining about the exact mechanisms in the brain that underpin it.
• Sleep has been understood to play a role in memory retention for over a century.
• Melatonin, a hormone naturally produced in the brain to induce sleep and regulate the circadian cycle, has been linked to improved memory in rodents.
• A recent study in mice has proposed that melatonin influences memory formation through the regulation of phosphorylation of proteins in parts of the brain responsible for memory.

How memories are formed has been a puzzle that has perplexed researchers for over a century, and there are still many questions that remain about the biological mechanisms that underpin them.

Perhaps because of this gap in understanding, there are no pharmacological interventions that can be taken to improve memory.

“Currently, there are no drugs that have been specifically approved for improving memory formation. While some prescription medications are used to improve memory in conditions like Alzheimer’s disease, they are not recommended for general memory enhancement in healthy adults,” Dr. Raj Dasgupta, chief medical advisor for Sleep Advisor, told Medical News Today.

Melatonin is a hormone naturally produced by the pineal gland in the brain’s center in response to darkness, and it helps regulate the circadian clock and sleep. Synthetic forms can be taken as a supplement to help induce sleep.

Its role in helping treat the symptoms of jet lag and insomnia in humans is the focus of research, according to the National Center for Complementary and Integrative Health.

Sleep has been linked to improved retention of memory for over a century, and it is thought that the brain state during sleep is optimized for memory consolidation, though the exact mechanisms underlying this link are unclear.

To explore whether melatonin and its derivatives had any effects on memory, researchers conducted experiments in mice and saw that the hormone promoted long-term memory by modulating protein phosphorylation.

Their results are published in NeuroReport.

How does melatonin improve memory?

In order to determine if the mechanism that underlies the link between melatonin and improved memory in mice was due to the activation of melatonin receptors or phosphorylation of other proteins involved in memory formation, researchers at Sophia University, Tokyo, Japan carried out a series of experiments on male mice.

They decided against using female mice in the experiments as they were concerned their fertility cycle would affect results.

Mice were first trained to find a ceramic object they hadn’t seen before while being exposed to a 12-hour light and 12-hour dark cycle.

This experiment was designed to measure long-term memory formation in mice by using the novel object recognition task (NORT).

Mice were familiarized with an experimental arena over three days. On the fourth day, two objects were introduced for a training phase. After 24 hours, one familiar object was replaced with a new object for the testing phase. Researchers recorded the duration of object exploration, which serves as an indicator of object recognition memory.

Following the initial memory test, the mice were administered either melatonin, a drug that binds to the melatonin receptor called ramelteon, a metabolic metabolite to melatonin called AMK, or a control treatment, with the effectiveness of these treatments on their memory performance being assessed after a day.

Researchers found novel object recognition increased in mice administered with melatonin, AMK, and ramelteon compared to controls.

The researchers then euthanized the mice and sampled the mice’s brains so they could look at the phosphorylation of proteins associated with memory formation in parts of the brain associated with memory creation, the hippocampus, and perirhinal cortex.

Phosphorylation is the addition of a chemical group to a protein, which affects its activity levels in biochemical reactions. They found that the phosphorylation of memory-associated proteins increased in the presence of AMK and ramelteon.

These 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.

These proteins are involved in receptor binding-related memory formation pathways and pathways not associated with receptor binding.

Why sleep is important for memory

Dr. Alex Dimitriu, double board-certified in psychiatry and sleep medicine, and founder of Menlo Park Psychiatry & Sleep Medicine, not involved in the study, explained to MNT the importance of sleep in memory formation.

“Sleep is the holy grail of memory and is behind a lot of the work I do with my patients,” he noted.

“Memories are formed in humans in several discrete steps. The first step is registration — this is the process of paying attention. Memories are next committed to short-term memory, and later with repetition, importance, and especially sleep, memories get converted into long-term storage. A lot of long-term memory formation occurs during slow wave sleep (deep sleep), in the first half of the night.”

– Alex Dimitriu

Due to the link between sleep and melatonin, the role of melatonin in memory creation has been explored. It remains unclear if the activation of melatonin receptors in the brain is responsible for improved memory formation or if other mechanisms are responsible.

There has previously been some research into whether melatonin improves different types of memory in rodents.

“A study published in 2021 found that melatonin improves short-term spatial memory in a mouse model of Alzheimer’s disease,” Dr. Dasgupta, who was also not involved in the study, said.

“Another study, published, in 2022 found that melatonin improved spatial learning and memory impairment in rats. These studies suggest that melatonin may be a potential treatment for memory problems, such as those associated with Alzheimer’s disease,” he told MNT.

Research yet to be carried out in people

The study was carried out in mice, and it is unclear if the results could be applicable to humans. However, further testing in humans could clarify the applicability of the research.

Dr. Clifford Segil, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, not involved in the current research, told MNT that“[d]oing research on how to improve memory in animals and then repeating similar tests in humans is a great idea.”

“If something is shown to have the potential to help animals form better long-term memories and the substance being given to the animals is without health side effects, these studies should be repeated in humans. Testing people to see if melatonin helps with memory would be interesting for me to review,” he said.

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