MODEL TO STUDY THE ROLE OF AVP, PKC, AND FOS IN THE SCN

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DESCRIPTION (Adapted from applicant's abstract): The suprachiasmatic nuclei (SCN) are the major "biological clocks" in mammals and control most circadian rhythms expressed by the animal. The role of AVP in the SCN is poorly understood, and the significance of Ca2+-dependent PKC isozymes in SCN function is not known. In the mouse, PKCalpha is present in all AVP-positive and many AVP-negative neurons. PKCalpha may play a role in signaling between AVP-positive and AVP-negative neurons within the SCN through the V1a class of receptors via phosphoinositol turnover and activation of PKC. Divergently selected mouse lines differ in the number of AVP, PKCalpha, and PKCbeta1 neurons in the SCN. The differences in the number of AVP, PKCalpha, and PKCbeta1 neurons in the SCN correlate with several circadian rhythm parameters of wheel-running activity and phase-delay responses to 15-min light pulses in constant darkness. Therefore, these lines represent a unique opportunity to investigate the functional role of AVP and Ca2+-dependent PKC isozymes and light transduction pathways in the SCN by using within-species differences in neuroanatomy and circadian behavior. The following hypotheses will be tested: (1) PKC immunoreactivity is restricted to a distinct group of neuronal phenotypes that also differ among the selected lines. (2) The lines differ in the circadian rhythms in AVP and PKC immunoreactivity in the SCN. (3) The magnitude of the phase-delay response is proportional to the number of cells in the SCN that exhibit Fos induction after a light pulse. (4) Differences in AVP immunoreactivity in the SCN among the lines are correlated with variance in plasma glucocorticoid rhythms. (5) Behavioral differences among the lines are due to different levels of PKC in the SCN. Single and double labeling immunocytochemistry of brain sections containing the SCN will be used. In addition, the variance in plasma glucocorticoid rhythms among the lines will be measured. It will also be determined whether chronic administration of a Ca2+-dependent PKC inhibitor into the SCN can alter circadian parameters of wheel-running activity. This proposal addresses the functional significance of key regulatory mechanisms within the SCN influencing physiological and behavioral traits. It will contribute to the general understanding of how the circadian clock in mammals adapts individual to the earth's day-night cycle and, therefore, will advance issues related to human health.