Disruption of the circadian clock, the 24-hour cycle of waking and sleeping, can increase the risk of a range of illnesses and can exacerbate stress, anxiety and mood disorders, including bipolar disorder, major depression and seasonal affective disorder. Dr. Gamble and her colleagues are working to decipher how the circadian clock works and how its rhythm gets thrown off balance.
Within the hypothalamus region of the brain (located just above the brain stem) is a smaller region called the suprachiasmatic nuclei (SCN), which is the body’s master clock, regulating sleep, metabolism and the production of hormones. When light enters through the eye it travels down the optic nerve to the SCN. The neurons in the SCN have high activity during the day and low activity at night. There are body clocks in the heart, lymphocytes, liver, lung, spleen and fat cells, but SCN is the only one that receives input directly from the eye and synchronizes all the clocks. Trouble can arise when something desynchronizes them.
Many genes are involved in circadian rhythm. Two important genes are clock and period (per). A feedback loop starts when clock activates per, which then feeds back to turn off clock and complete the 24-hour cycle. Dr. Gamble is measuring circadian timing using mice genetically developed so that when per is activated, it initiates a chemical reaction comparable to the one in lightning bugs. This animal model makes it possible to remove the brain clock or other clocks and collect the photons—the light particles—coming off the tissue. It is also possible to reset the clock with light or with an SCN neurochemical called gastrin-releasing peptide, or GRP, which has the same effect as light.
Another player, an enzyme called GSK-3, appears to make the feedback loop bigger or more robust. GSK-3 is of particular interest since it is a target for lithium, a common drug used to treat bipolar disorder. While studying the effect of GSK-3 in laboratory mice, Dr. Gamble has begun clinical research, studying shift workers, who tend to suffer from a chronic jet-lag state and have a high rate of mood disorders. Among her findings is a genetic mutation that seems to help some workers cope better than others with the disruption of circadian rhythm.
In partnership with University of Alabama at Birmingham
Karen Lynnette Gamble, Ph.D.
Assistant Professor of Psychiatry and Behavioral Neurobiology
Department of Psychiatry and Behavioral Neurobiology
University of Alabama at Birmingham