The mammalian suprachiasmatic nucleus (SCN) is the locus of a """"""""circadian clock"""""""" that regulates rhythms in both 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. The mystery starts with the fact that circadian rhythmicity is a cellular property, but that 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. Our research focuses on understanding SCN organization. We have found that some SCN neurons, including GRP cells of the 'core' in mouse SCN are not detectably rhythmic (assessed by clock gene expression and electrical activity), but respond to photic input. Other SCN neurons, including vasopressin-containing cells of the 'shell' SCN are rhythmic. Because both hamster and mouse SCN share these characteristics, we propose that it is a general feature of mammalian brain clocks. We now propose to analyze the SCN in a biologically important preparation. In mouse, testicular hormones play a major role in regulating locomotor activity; gonadectomy produces a lengthening of free-running period, a loss of precision and complete loss of the daily activity onset bout. We will study the cellular basis of this response to understand the network organization of the SCN. Preliminary studies indicate that GRP cells contain androgen receptors (AR), have a characteristic pattern of electrical activity, and identifiable morphological features and projections. We plan to examine how gonadal hormones act on AR-containing cells to regulate circadian rhythmicity at the behavioral, tissue and cellular/molecular levels. We hypothesize that tonic androgen-dependent input of GRP cells onto Per1 bearing oscillators is necessary for the behavioral responses seen in the intact mouse, and that gonadectomy produces a loss of pacemaker output, with resulting changes in behavior. To determine the mechanisms whereby testicular hormones act, we will use the powerful analytic tools available in our 3 colonies of transgenic mice bearing a reporter for either the Per1 gene (Per-GFP mice), the gastrin releasing peptide (GRP-GFP mice), or a neuronal and nuclear label for androgen receptor (AR mice).
5 specific aims will be examined 1) the role of androgens in the regulation of behavioral circadian rhythms; 2) the phenotype of AR-containing cells in the SCN; 3) androgen effects on SCN neuronal plasticity, 4) clock gene expression and 5) electrophysiological responses of AR-containing and rhythmic Per-expressing cells. The broad significance of this work lies in understanding how the SCN regulates rhythmicity using androgen-mediated changes as an analytic tool. The work also contributes to a better understanding of circadian changes associated with puberty, andropause, sleep regulation and some aspects of sex differences. ? ? ?
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