Desynchronization of normal circadian functions induced by shifts in the normal sleep-wake cycle, irregular work patterns or various disease conditions is known to adversely affect productivity, increase the risks of accident and affect emotional/psychological state. Progress towards developing treatments for ameliorating the debilitating effects of circadian desynchrony lies in understanding the neurological basis for the regulation of endogenous circadian rhythms. The broad goal of the proposed studies is to characterize the roles of specific cell surface components in regulating cell-cell interactions within the circadian clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The polysialylated NCAM (PSA-NCAM) is a cell surface component which plays key roles in neurogenesis and is retained in regions of the adult brain that have the potential for neural plasticity. The recent demonstration of its robust expression by SCN cells had led to the hypothesis that embryonic-like plastic morphological rearrangements may be important to circadian clock function, such as its ability to be reset on a daily basis by light. The proposed studies, therefore, are designed to study the role(s) of PSA-NCAM in the SCN using biochemical, morphological and behavioral endpoints. We will utilize transgenic mice that lack PSA-NCAM in the adult brain and an enzyme (endo N) that specifically removes PSA from NCAM in vivo. We will first determine at the light- and electron-microscopic levels which cells in the SCN express PSA-NCAM and whether there are daily fluctuations in its expression. We will then assess the effects of PSA-NCAM deletion on time-keeping characteristics of the circadian locomotor rhythm, including rhythm generation and entrainment. Finally, we will examine the effects of PSA removal on morphological indices of SCN cell-cell interaction, including changes in synapses and neural appositions. Results from these studies will provide important insight into the dynamics of cell-cell communication in the mammalian SCN circadian clock.
