Circadian rhythms affect human health and well-being by temporally organizing biological processes and fitting them to a 24 hour period. In mammals, circadian rhythm generation and organization are regulated by oscillatory networks in the heterogeneous suprachiasmatic nucleus (SCN) of the hypothalamus. Acute light resets the phase of these networks at night by an incompletely understood mechanism that involves changes in the transcriptional status of the immediate early gene c-fos and the clock gene Per1 in individual SCN cells. Neuropeptides, which anatomically define the SCN's functionally distinct core and shell subregions, have also emerged as important players in this light response pathway. The following set of studies examines how one such neuropeptide, vasoactive intestinal peptide (VIP), contributes to the gene expression changes across the SCN network during a successful phase shift. Experiments show that in response to a phase shifting light pulse, mice genetically deficient in VIP: 1) have acute, blunted molecular responses of c-FOS and Per1 in the SCN, 2) do not sustain gene expression changes in c-FOS and Per1 across SCN cells over time, and 3) lack gene expression changes of c-FOS and Per1 specifically in the SCN shell. Because these effects of VIP may be either acute or chronic due to an organizational or developmental role for VIP, experiments were also carried out to identify anatomical changes in the SCN of mice genetically deficient in VIP. Results suggest that specific changes to the light-input side of the circuit are altered when VIP is absent, indicating an organizational role for this neuropeptide. These changes include increased retinal afferent terminal branching and decreased androgen receptor expression in the retino-recipient region of the SCN. Interestingly, there did not appear to be changes in intra-SCN connectivity in mice lacking VIP, as determined by analysis of Golgi impregnated neurons. These data together suggest that VIP acts not only acutely to affect photic signaling, but it also plays a role in the structuring of the SCN to allow for the efficient flow of photic phase resetting information from retinal inputs across the circadian system.

mammals, the circadian oscillators that drive daily behavioral and endocrine rhythms are located in the hypothalamic suprachiasmatic nucleus (SCN). While the SCN is anatomically well-situated to receive and transmit temporal cues to the rest of the brain and periphery, there are many holes in our understanding of how this temporal regulation occurs. Unanswered questions include how cell autonomous circadian oscillations within the SCN remain synchronized to each other as well as communicate temporal information to downstream targets. In recent years, it has become clear that neuropeptides are critically involved in circadian timekeeping. One such neuropeptide, vasoactive intestinal peptide (VIP), defines a cell population within the SCN and is likely used as a signaling molecule by these neurons. Converging lines of evidence suggest that the loss of VIP or its receptor has a major influence on the ability of the SCN neurons to generate circadian oscillations as well as synchronize these cellular oscillations. VIP, acting through the VPAC2 receptor, exerts these effects in the SCN by activating intracellular signaling pathways and, consequently, modulating synaptic transmission and intrinsic membrane currents. Anatomical evidence suggests that these VIP expressing neurons connect both directly and indirectly to endocrine and other output targets. Striking similarities exist between the role of VIP in mammals and the role of Pigment Dispersing Factor (PDF), a functionally related neuropeptide, in the Drosophila circadian system. Work in both mammals and insects suggests that further research into neuropeptide function is necessary to understand how circadian oscillators work as a coordinated system to impose a temporal structure on physiological processes within the organism./>