Building a Mammalian Brain Clock

The mammalian suprachiasmatic nucleus (SCN) is the locus of a “circadian clock” that regulates rhythms in physiology and behavior. While this function is well established, it is not known how the 20,000 neurons that comprise the nucleus are synchronized and consequently generate a coherent output signal. Circadian rhythmicity is a cellular property, but individual SCN cells have different endogenous periods and phases. Heterogeneity among SCN neurons is also seen in inputs and outputs, neuronal morphology, peptides and “clock” gene expression. To understand SCN organization, we developed a mathematical model to account for the coherent expression of rhythmicity in the tissue as a whole, and reveal novel general features of the mammalian brain clock system. In our account, SCN “gate” neurons synchronize oscillators. Physiologically, gate cells represent GRP cells of the ‘core’ in SCN, which are not detectably rhythmic (assessed by clock gene expression and electrical activity), but respond to photic input. Oscillator cells include rhythmic vasopressin‐containing neurons of the ‘shell’ SCN. Furthermore, we find that internal and external phase setting cues converge on gate cells. Thus in mouse, gonadal hormones play a major role in regulating locomotor activity. AR‐containing cells are highly localized to the core SCN region. Gonadectomy produces lengthening of free‐running period, loss of precision and loss of the night‐time onset bout of activity. Analysis of the cellular basis of the androgenic effects permits deconstruction network organization of the SCN, and reveals how the network is modulated by internal and external stimuli. Because inputs, outputs and functions of the suprachiasmatic nucleus are quite well understood, studies of the circadian system promise to reveal general principles of circuit organization in the mammalian brain. Supported by NINDS 37919