The Jekyll and Hyde of hormones: A daytime savior turns a menace at night.

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Things look different after dark.


What do you do when a naturally occurring hormone in your body turns against you? What do you do when that same hormone melatonin is a popular supplement you take to help you sleep? Some intriguing answers were provided by Professors Gregory Cahill and Gregg Roman and their graduate students Oliver Rawashdeh and Nancy Hernandez de Borsetti from the Department of Biology and Biochemistry at the University of Houston.

Frequently called the hormone of darkness, melatonin is a hormone the body produces that may regulate sleep patterns. In almost all organisms tested, the natural levels of this hormone are high during the night and low during the day. Melatonin is also a very powerful antioxidant.

Unlike vitamin C or glutathione, which are only active in aqueous (watery) phase and vitamin E, which is only active in lipid (oily) phase, melatonin is effective in both aqueous and lipid phases. Thus, many people take melatonin supplements to fight jetlag, balance out seasonal affective disorder, and regulate dementia.

Melatonin, however, turned out to have a dark side after dark. The University of Houston used a model organism, the zebrafish (Danio rerio), and found that melatonin directly inhibits memory formation at night. The study was initially concerned with the mechanism by which the biological clock controls the formation of new memories. The researchers found the zebrafish capable of learning very well during the day, but a very slow learner at night. The experiments were performed using zebrafish for several reasons. They're small and breed in large numbers (thereby being inexpensive to use), and they are diurnal, having the same activity rhythms as people. Zebrafish are most active during the day and less active at night, whereas many other vertebrate model systems, such as rodents, are nocturnal. Thus if one is interested in how the biological clock regulates cognitive function in humans, one should use a model system that reacts to the clock the same way people do.

More than two years worth of work, including the discovery that the ability to learn and remember was controlled by an endogenous (or internal) clock originating within the zebrafish, led Cahill and his colleagues to hypothesize that melatonin may be responsible for poor learning and memory formation during the night. In order to test whether melatonin was involved in inhibiting nighttime learning and memory formation, they treated the zebrafish during the day with melatonin. Interestingly, melatonin failed to affect learning, but dramatically inhibited the formation of new memories.

The next step was to inhibit melatonin signaling during the night with a melatonin receptor antagonist and test for effects on memory formation. According to Dr. Roman, The results were, excuse the expression, like night and day. We saw dramatic improvements in nighttime memory formation by inhibiting melatonin signaling, indicating that the reason the zebrafish did not form memories at night was because of the melatonin hormone.

Next, with the pineal gland being the primary source of melatonin in fish and in people, Graduate student Oliver Rawashdeh removed the gland from the fish and found they could now form memories during the night. Removing this melatonin-producing gland allowed the researchers to alleviate the hormone's negative side effects, further demonstrating that melatonin inhibits the formation of new memories during the night.

With these findings, the University of Houston researchers hope to have a handle on separating the beneficial effects of melatonin (the antioxidant properties) from its negative effects. The benefits include the slowing down of some forms of neurodegeneration, such as in Parkinson's and Alzheimer's, and stopping DNA damage, which may prevent certain cancers. And, since the positive antioxidant effects are direct and independent of receptor signaling, there is hope that by removing the melatonin receptor signaling mechanism, one may be able to combat the negative effects of melatonin on cognitive function without affecting the benefits.

Additionally, the University of Houston scientists hope that by inhibiting melatonin signaling with receptor antagonists may help many people who need to perform nighttime cognitive tasks. Among the people that may benefit from this study are students studying for finals, airplane pilots, ER physicians, and nightshift workers.

The value of melatonin as a supplement is largely due to its antioxidant properties, Roman said. The use of melatonin receptor antagonists will not affect this attribute, but may alleviate an important side effect on nighttime cognitive function.

The article was published in the journal Science on November 16, 2007, and is entitled Melatonin Suppresses Nighttime Memory Formation in Zebrafish."