The work of a NARSAD Young Investigator could help cast a new light on how a timing system in our body responsive to the day/night cycle generated by the rotation of the Earth is implicated in seasonal depression. Part of the mystery about Seasonal Affective Disorder (SAD) is why only some people are affected - less than 10 percent of the population even in northern latitudes with short winter days and long nights; and young women more than others.

But before those puzzles can be solved, more basic questions about the mechanisms that give rise to SAD need to be addressed. Xiangzhong Zheng, Ph.D., a 2010 NARSAD Young Investigator and research assistant professor of neuroscience at the University of Pennsylvania, is interested in SAD and other biological disturbances that are rooted in the phenomenon called circadian rhythm.

As Dr. Zheng explains, "circadian" literally means "about a day" - a reference to the internal body clock that times many aspects of our daily life in close approximation to the 24-hour cycle of light and dark that most (if not all) living things on Earth respond to.

Using the "core clock" in the brain of the humble fruit fly as a model of the one that sets the rhythms of our own lives, Dr. Zheng is adding to knowledge already obtained about the brain areas, genes and proteins whose workings "set" our master biological clocks.

What is perhaps most intriguing about Dr. Zheng's work is that it takes us down a new pathway - literally, a biological pathway - whose relevance to SAD is less intuitive than pathways directly involved in the body's response to light and dark. In 2008, Dr. Zheng was part of a team that examined an organ of the fruit fly called the fat body, which is the rough equivalent of the liver in humans. It's a place where energy-rich glycogen and fatty lipids are stored.

The team demonstrated that disruptions of the circadian clock in these fat body cells make flies abnormally sensitive to hunger, resulting in reduced stores of glycogen. Dr. Zheng says this interests him in part because of something well known about people with SAD: some of those with the disorder, whose internal clocks are out of synch, respond by craving and eating large amounts of carbohydrates.

Dr. Zheng credits NARSAD with helping make certain that his promising career has gotten off to "a good start." "This Young Investigator award is enabling me to collect preliminary data which we'll use later in applications for much larger projects funded by the federal government," he says.

Dr. Zheng and colleagues are currently investigating the cellular pathway called AKT-TOR, which is involved in regulation of the metabolism of cells. Since internal clocks coordinate the way our bodies use energy, defects in those clocks may be tied to metabolic disorders, the most well known of which is diabetes. The focus of Dr. Zheng's interest right now is how genes whose expression is important in metabolism in turn "feed back" to affect the cellular clocks that drive behavioral rhythms.

The circadian timing system is, to use a term favored by scientists, "highly conserved": it has proven so important to survival that it has been preserved throughout evolutionary time, from the simplest creatures, to the fly, to humans. Dr. Zheng's work on pathways in the fly are already giving us insights into the linkages between body clocks, behavior and the relative presence or absence of light, but also, more complex interrelationships between internal clocks and the ways organisms regulate their metabolism. A more complex picture of a clock-related disorder like SAD is likely to emerge from this pathbreaking work in the coming years.