GENETIC APPROACH TO CIRCADIAN RHYTHMS IN DEPRESSION

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DESCRIPTION (applicant's abstract): Depression has been linked to abnormalities in circadian rhythms in humans and in animal models of depression; however, it is unknown whether a dysfunctional circadian pacemaker can contribute to the development/or severity of depressive symptoms or if circadian rhythm alterations are secondary to the primary cause of the depression. Our laboratories have developed a line of mice harboring a mutation in the Clock gene, a gene that is crucial to normal functioning of the circadian pacemaker. When placed in constant darkness/constant light, Clock mutant heterozygotes exhibit a lengthened period of 25 hours and Clock mutant homozygotes exhibit a lengthened period of 27-28 hours and become arrhythmic after about three weeks in constant conditions. Preliminary studies of sleep in Clock mutant mice have shown that they have decreased total sleep which can be attributed to a decrease in sleep during the light period, but no overall changes in N-REM and REM sleep. The discovery of the Clock mutant mouse as well as having the capability to record sleep from mice puts us in a unique position to test two hypotheses: 1) whether alterations in the circadian pacemaker can contribute to the development of and/or the severity of depressive-like symptoms in an animal model of depression, and 2) whether sleep deprivation, known to have an anti-depressive effect, will attenuate depressive-like symptoms in mice with an altered circadian pacemaker. To test these hypotheses, our laboratory has already established a model of chronic, unpredictable stress in mice and has validated the use of the pedestal-over-water technique as a method of sleep deprivation in mice. These experiments will further the understanding of the relationship between circadian rhythms and depression, thus providing insight on the development of novel therapeutic treatments of depression.