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Melatonin’s role in memory formation

A recent study published in NeuroReport titled Effects of melatonin on phosphorylation of memory-related proteins in the hippocampus and the perirhinal cortex in male mice has news outlets taking notice. The researchers of this study have contributed to helping explain the mechanism of how melatonin impacts memory.


This animal study aimed to investigate how melatonin (the hormone secreted from the pineal gland), ramelteon (a drug that binds and activates melatonin receptors), and AMK (melatonin’s biological metabolite) impacted phosphorylation of memory-related proteins. Phosphorylation is the addition of a phosphate group to a molecule and is a critical process needed for cells and the regulation of protein function.


In this study, the phosphorylation of five protein associated with memory were explored:

  1. Extracellular signal-regulated kinase (ERK)

  2. Calcium/calmodulin-dependent kinase IIα (CaMKIIα)

  3. Calcium/calmodulin-dependent kinase IIβ (CaMKIIβ)

  4. Calcium/calmodulin-dependent protein kinase IV (CaMKIV)

  5. cAMP-response element binding protein (CREB)

Highlights of the study design include:

  • Male mice were assessed using NORT --novel objection recognition task experimentation.

  • The mice were exposed to 12 hours of light and 12 hours of dark.

  • After the initial memory test, a single administration of melatonin, ramelteon, or AMK was given (1 mg/kg) and compared against a control.

  • Female mice were not tested due to the impact the reproductive cycle may have on results.


Experiment 1: The recognition of a novel object was significantly increased in all three treated groups compared to the control group, suggesting the promotion of long-term memory formation.  

  • Melatonin: P< 0.001

  • Ramelteon: P<0.001

  • AMK: P<0.01

Experiment 2: After euthanasia, the researchers sampled the mice’s brains to look at the phosphorylation of proteins found in the hippocampus and perirhinal cortex (The two areas where memories are formed.)

MLT for Memory.png

                                    There was no impact on CaMKIV for any treatment group.


In summary, this study found that a single dose of ramelteon, AMK, and melatonin promoted long-term memory formation (LTM).


The authors noted that melatonin “increased the activity of memory-related signaling pathways” and that it is “likely that melatonin promotes LTM formation,” acknowledging that more research will be needed on this topic. Further, the researchers believe this study will contribute to developing new drug therapies to help improve memory function.

Written by: Kim Ross, DCN

Reviewed by: Deanna Minich, Ph.D.

Updated September 8, 2023

Article Reference: 

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 Jun 7;34(9):457-462. doi: 10.1097/WNR.0000000000001911. Epub 2023 May 10. PMID: 37161988.

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