The suprachiasmatic nucleus (SCN) of the anterior hypothalamus has long been considered a master circadian pacemaker that drives rhythms in physiology and behavior in mammals. The recent discovery of self-sustained and cell-autonomous circadian oscillators in peripheral tissues has challenged this position. This dissertation tested the general hypothesis that the SCN has properties that distinguish it from other oscillators, thereby positioning it atop a circadian hierarchy. The general approach was to compare the consequences of altering the molecular circadian clock on tissue-autonomous rhythmicity in mice. In the first experiments, the role of the SCN as a master clock was tested by manipulating the expression of a circadian gene in the brain. Specifically, the expression of the short period tau mutation of casein kinase-1-epsilon (CK1ε) was controlled in an anatomically- and a temporally-specific manner via a tetracycline transactivator regulatory system. This inducible expression of CK1εtau affected the period of activity rhythms when expressed in the SCN, but did not affect the tissue-autonomous rhythmic properties in the peripheral tissues. Second, real-time bioluminescence imaging of tissues from PER2::LUCIFERASE mice revealed that period and phase of different circadian oscillators were tissue specific. Various circadian gene mutations (Cry1-/-, Cry2-/-, Cry1-/-;Cry2-/-, Clock∆19/∆19) produced little difference in rhythmic properties between the SCN and peripheral oscillators, although Cry1-/- SCN had more robust and persistent rhythms compared with the periphery. Third, the loss of Bmal1, which produces behavioral arrhythmicity, eliminated rhythms in the peripheral tissues, but not in the SCN. Bmal1-/- SCN rhythms were highly variable in period and amplitude, fitting a stochastic, but not a deterministic model of rhythm generation. Unlike mutations in other circadian genes, rhythmicity was completely abolished in single SCN neurons in Bmal1-/- mice, indicating that rhythms in Bmal1-/- SCN tissue are a property of the tissue organization rather than an averaging of single-cell autonomous rhythms. The SCN, therefore, has a unique anatomical organization that contributes to long-term stability and temporal organization of the circadian hierarchy.

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus has long been considered a master circadian pacemaker that drives rhythms in physiology and behavior in mammals. The recent discovery of self-sustained and cell-autonomous circadian oscillators in peripheral tissues has challenged this position. This dissertation tested the general hypothesis that the SCN has properties that distinguish it from other oscillators, thereby positioning it atop a circadian hierarchy. The general approach was to compare the consequences of altering the molecular circadian clock on tissue-autonomous rhythmicity in mice. In the first experiments, the role of the SCN as a master clock was tested by manipulating the expression of a circadian gene in the brain. Specifically, the expression of the short period tau mutation of casein kinase-1-epsilon (CK1ε) was controlled in an anatomically- and a temporally-specific manner via a tetracycline transactivator regulatory system. This inducible expression of CK1εtau affected the period of activity rhythms when expressed in the SCN, but did not affect the tissue-autonomous rhythmic properties in the peripheral tissues. Second, real-time bioluminescence imaging of tissues from PER2::LUCIFERASE mice revealed that period and phase of different circadian oscillators were tissue specific. Various circadian gene mutations (Cry1-/-, Cry2-/-, Cry1-/-;Cry2-/-, Clock∆19/∆19) produced little difference in rhythmic properties between the SCN and peripheral oscillators, although Cry1-/- SCN had more robust and persistent rhythms compared with the periphery. Third, the loss of Bmal1, which produces behavioral arrhythmicity, eliminated rhythms in the peripheral tissues, but not in the SCN. Bmal1-/- SCN rhythms were highly variable in period and amplitude, fitting a stochastic, but not a deterministic model of rhythm generation. Unlike mutations in other circadian genes, rhythmicity was completely abolished in single SCN neurons in Bmal1-/- mice, indicating that rhythms in Bmal1-/- SCN tissue are a property of the tissue organization rather than an averaging of single-cell autonomous rhythms. The SCN, therefore, has a unique anatomical organization that contributes to long-term stability and temporal organization of the circadian hierarchy.