In the many processes of life, timing is everything. It affects not only when we sleep and when we're awake, but our eating and nutrition, our ability to work and perform complex cognitive tasks, the autonomous functions of the heart and other organs, even our fertility. Studying the natural clocks and rhythms that govern life on the genetic level is the specialty of Amita Sehgal, PhD, the John Herr Musser Professor of Neuroscience. Her chief model is the fruit fly, which is providing keen insights into sleep in its most basic form. 

One of the most important clocks of the body is in the liver. Fruit flies have an equivalent organ called the fat body, also containing its own clock. When Sehgal and her research team purposely desynchronized the fat body clock with the master clock by feeding the flies at irregular times, they found that fruit flies actually produce fewer eggs than flies that are kept under normal conditions, implying a connection between this cyclical disruption and fertility.

Sehgal's lab is also probing into the previously inaccessible "black box" of the molecular pathways that underlie the physiological processes that connect the brain clock to sleep. Her team found that in the fruit fly, one of these connections involves a microRNA (miRNA) which works through the Upd protein to regulate the JAK/STAT pathway. The Upd protein appears to play a crucial role in maintaining a normal rest/activity rhythm, with a miRNA called miR-279 controlling Upd. 

Although fruit flies, like humans, are naturally diurnal (active during the day, sleeping at night), Sehgal uncovered a mechanism that may reverse that cycle through increased levels of the dopamine neurotransmitter, similar to a phenomenon called "sundown syndrome" that occurs in people with dementia or other cognitive impairments. The elevated dopamine is associated with increased activity of the CRY (cryptochrome) photoreceptor, also normally inactive at night.

The timing of when we sleep versus are awake is controlled by cells in tune with circadian rhythms of light and dark. Most of the molecular components of that internal clock have been worked out, but how much we sleep is regulated by another process called sleep homeostasis, like that in the roundworm studies. The Sehgal lab found a new protein involved in the homeostatic regulation of sleep in the fruitfly. They conducted a screen of mutant flies to identify short-sleeping individuals and found one, which they dubbed redeye. These mutants show a severe reduction in the amount of time they slumber, sleeping only half as long as normal flies. The redeye gene encodes a subunit of the nicotinic acetylcholine receptor. This type of acetylcholine receptor consists of multiple protein subunits, which form an ion channel in the cell membrane, and, as the name implies, also binds to nicotine. Although acetylcholine signaling -- and cigarette smoking -- typically promote wakefulness, the particular subunit studied is required for sleep in Drosophila.

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