:: By Lydialyle Gibson

:: Photo by Hou Cyril/Shutterstock

Investigations ::

Most people think of melatonin as a hormone supplement: a tablet before takeoff can mean escape from jetlag, and a dose at bedtime can help hasten sleep. But for Brian Prendergast, assistant professor in psychology and an Institute for Mind and Biology researcher, melatonin constitutes “the internal representation of time.” Secreted nightly by the pineal gland, the hormone alerts birds, lizards, and mammals to approaching mating seasons and helps them keep track of hibernation deadlines. Melatonin is the reason the Siberian hamsters in Prendergast’s lab, isolated from the outdoors, continue following seasonal eating, sleeping, and mating patterns, as long as the lights go on and off at certain intervals. “We have this ethereal concept of what time is,” Prendergast says, “but we actually know its biological basis.”

For a decade Prendergast has studied the internal clocks that allow animals to tell the time of day without a watch and the time of year without a calendar. Tissues in the brain and throughout the body calculate the length of a melatonin signal—how long the hormone is secreted—to discriminate between summer’s eight-hour nights and winter’s 16-hour ones, a process Prendergast outlined in an award-winning 2005 Hormones and Behavior article. When darkness begins to lengthen in late summer and early fall, so do melatonin signals. Animals, aware that cold weather is coming, halt reproduction; in Siberian hamsters, the testes and uteri regress as spermatogenesis and ovulation cease.

Then in mid or late winter, as nights and melatonin signals get shorter, animals prepare to mate. “It’s very important to get the timing right,” Prendergast says. Otherwise animals lose precious weeks. “It’s not just the physiological changes that have to take place; some animals need to migrate back to breeding grounds. ... The way animals anticipate coming environmental change is by measuring the length of day”—in other words, by determining whether melatonin is waxing or waning. “If you give fake melatonin signals, you can trick animals into thinking it’s summer or winter when it’s not,” he says. Take away melatonin altogether, by removing the pineal gland, and “you abolish the animal’s ability to internalize day length.”

The mystery Prendergast’s research aims to unravel is precisely how melatonin interacts with the tissues that detect it. “There’s a big disconnect there,” he says. “We know the location of melatonin receptors in the brain”—the thalamus and hypothalamus—“and we know that the pituitary gland controls the reproductive system.” What’s less understood is the mechanism between those two that transforms a long melatonin signal into a directive that shrivels the testes and uterus. “What genes are expressed in a summer brain,” he says, “versus a winter brain?”

To find out, Prendergast and colleagues set up genetic experiments. In one, detailed in a 2002 Proceedings of the National Academy of Sciences, they used cDNA microarrays to examine thousands of hypothalamic genes at once. They found seasonal changes in a series of genes whose common function was to transport thyroid hormones. Later the researchers discovered that chemically disabling Siberian hamsters’ thyroid glands would accelerate their seasonal clocks. “We think thyroid hormones”—which affect body weight, body temperature, metabolism, and heart rate—“might function as a link,” he says. “Right now we’re in the process of delivering thyroid hormones directly to the brain in an effort to reset the seasonal clock.”

Four years ago Prendergast embarked on a related puzzle, with implications for human disease: seasonal changes in the immune system. Flu is usually widespread between December and February, while whooping cough typically peaks in July. “We don’t really know why,” he says. Immune-related measurements are complex; “you can’t just unilaterally shut down your immune system the way animals shut down reproduction.” Instead researchers scrutinize particular components: T-cells, B-cells, natural killer cells. “In short days, some of them go up and some go down. ... Animals are better at healing wounds during the summer, but they’re better during winter at developing an inflammatory response” to bacteria or other toxins. 

Yet the immune system’s seasonal mechanism remains mysterious. “We’ve learned a lot about how time is internalized,” he says, “but 95 percent of the studies are of the reproductive system.” Immune responses to daylight changes are not identical, which makes Prendergast wonder if only one internal clock keeps time in the central nervous system. “Or,” he asks, “might there be separable seasonal clocks, one that interprets information for the reproductive system, and another for the immune system?”

The latter seems more probable, although melatonin is central to both immunity and reproduction: when Prendergast removed hamsters’ pineal glands, the immune sys-tem—not just the reproductive system—reacted. But when he delivered a long, winter melatonin signal to the hypothalamus, the hamsters’ reproductive organs atrophied while summer immune function remained intact, indicating “a segregation of pathways that process melatonin.”

Prendergast hypothesizes that those pathways may diverge because immune function requires less time to adapt. “Plenty of data,” he says, “show that an animal can cut the number of white blood cells in circulation by about half in ten or 15 minutes. ... For all we know, the immune system can exhibit a whole range of seasonal changes in a day.” Reproduction doesn’t adjust so quickly; regrowing testes, for instance, takes hamsters two months. “We’re starting to reexamine basic assumptions of seasonal time.”