Robert Barker/University Photography

Patrick W. Concannon, an endocrinologist and reproductive biologist in the Department of Physiology, holds a woodchuck (groundhog) involved in studies of circannual cycles. Robert Barker/University Photography

Knowing why the groundhog comes out of hibernation in early February may have more import than predicting winter's end, Cornell researchers have found.

Groundhogs have more dramatic annual biological rhythms than nearly all other mammals and are a perfect animal model for studying them. In fact, groundhogs, also known as woodchucks, may provide key clues into better understanding cancer and cancer treatment, blood cell functions, brain activity and mental health.

For more than 15 years, Cornell researchers have been raising the world's only disease-free woodchucks (Marmota monax) to study hepatitis B infection and the liver cancer it can cause. Those studies, supported by the National Institutes of Health, have resulted in many advances in understanding liver disease, including proof that hepatitis B virus infection is the proximate cause of liver cancer and that immunization against the virus can prevent liver cancer.

Recently, however, Patrick W. Concannon, an endocrinologist and reproductive biologist in the Department of Physiology in Cornell's College of Veterinary Medicine, has been focusing on the woodchuck's dramatic seasonal cycles that profoundly alter the rodents' reproductive activity, food intake, basal metabolism, body fat and total body weight from season to season. During the year, for example, woodchucks vary their daily food intake by 2,000 percent, and both their body weight and metabolic rates increase up to 100 percent and then decline by 50 percent.

Concannon suspects that most mammals, including humans, have similar annual cycles. These cycles, he believes, are driven by hormonal signals, synchronized by annual changes in photoperiod, and influence functions such as metabolism, reproduction, hair growth, fat deposition and so forth.

To better understand annual cycles and how they might affect liver and fat metabolism, liver carcinogenesis, thyroid function, brain function and even obesity, Concannon has been experimenting with the circannual cycle of the woodchuck.

"The woodchuck may be the best mammalian species to study the underlying biological mechanisms of circannual cycles because its large body size allows collection of blood and tissue samples of adequate size, and we have already determined the husbandry, dietary and housing conditions to maintain it as a laboratory animal model in closed colonies with high rates of reproduction," Concannon said. And, Cornell scientists have a head start with their data on circannual changes in metabolic rate, thyroid hormone activity and prolactin secretion.

Other scientists had observed that the seasonal cycles of woodchucks did not vary when exposed to either short or long days. Concannon figured out why.

"We have found that woodchucks have very powerful endogenous cycles," Concannon said. "In other words, they undergo a series of seasonal changes which trigger one another and involve about a one-year cycle, even when there are no light cues to entrain them to 12 months."

He also has determined that the woodchuck cycles can be influenced by photoperiods but only if nature is mimicked more closely and the animals are exposed each day to a slightly longer or shorter day. By exposing the woodchucks to computer-controlled lighting, with gradually lengthening or gradually shortening "days," Concannon has been able to entrain woodchucks to a circannual cycle as if they were living in Australia or South America and another group of woodchucks to an 8-month year.

Concannon's studies, which have recently been published in Biology of Reproduction, Laboratory Animal Science and the Journal of Experimental Zoology, have been the first to conclusively demonstrate that the endogenous circannual cycle in these animals, and probably in all temperate species, are entrained by photoperiods and that daily changes in light are more critical than day length.

The endogenous cycles of the woodchuck are so strong that even in the laboratory, where the temperature is maintained at 70 degrees year-round with ample food and water, some woodchucks still stop eating and hibernate because of the underlying biology of the circannual cycle, Concannon said.

"And guess when they stop hibernating? Right around Groundhog Day in early February," he said. He suspects that their urge to hibernate is driven by decreasing 'day-length' but that the effectiveness of short days (or even total darkness underground) wears off over time. When that happens, the processes are reversed, and the rodents emerge from hibernation with a very healthy appetite and high energy, which are further stimulated by the increasing day lengths that occur in late winter and spring.

"The implications of better understanding these circannual rhythms is very significant for human medicine," said Concannon, who pointed out that recent research clearly suggests that humans have circannual cycles, although not as profound as those in the woodchuck. "These cycles include changes in blood chemistry during the year and changes in hormone secretion. Our cycles, like those of woodchucks, are most likely also entrained by photoperiod, although such entrainment may be less than precise due to our exposure to artificial lighting schedules at home, work and play."

Concannon hopes that, by studying the profound circannual changes in body function in the woodchuck, scientists can better understand the underlying changes in brain chemistry, body metabolism and hormone secretion that have evolved as part of the biology of circannual cycles and that probably exist in most species. The woodchuck also may provide clues to the basis of circannual changes in body function that just now are being recognized in human clinical research. For example, there are circannual changes in the rate of DNA synthesis and cell division in bone marrow and intestinal cells in humans, and that has implications in the use, efficacy and side-effects of chemotherapy used to treat cancer.

"Clinical studies of blood cells and blood components in humans have revealed circannual changes in the volume of red blood cells, hemoglobin, hematocrit, white blood cell function, blood-clotting proteins, tumor marking proteins in cancer patients, hormone receptors on blood cells, blood protein levels and cholesterol levels in different blood fractions," Concannon said. "Human brain activities also show circannual cycles. Circannual rhythms have been reported for the amount and percent of REM-sleep, the brain's serotonin-neurotransmitter system, the occurrence of migraine attacks and even the size of vasopressin-secreting neurons in the supra chiasmatic nucleus [the nucleus that appears to control circannual cycles]."

Mental health also has a seasonal component, as seen in the winter mental depression of seasonal affective disorder (SAD). Those patients have profound seasonal changes in taste sensation, appetite and food intake, Concannon said. Normal individuals also appear to have circannual changes in basal metabolism, energy level and appetite, as well as in metabolic hormones like prolactin.

Concannon said that seasonal changes also occur in blood pressure, the incidence of stroke and the secretion of kidney and adrenal hormones that most affect blood pressure (renin and aldosterone). They also exist for the major adrenal stress hormone (cortisol), thyroid secretion and secretion of the pituitary hormone that controls the thyroid.

"Even reproductive function has a circannual cycle," Concannon said. "Men have circannual rhythms in testosterone, pituitary hormones controlling testis activity, sperm counts and semen chemistry. Circannual patterns have been reported for the level of hormone receptors in breast cancer, for the occurrence of premature births and for the chemistry of the fluid in ovarian follicles."