Novel SCN-OVLT portal system: Dissecting Anatomical and Functional Properties

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PROJECT SUMMARY The suprachiasmatic nucleus (SCN), the locus of the brain’s circadian clock, plays a critical role in mediating circadian rhythmicity of numerous important functions. A growing body of work supports that these actions are not only mediated via hard-wired efferent projections from the SCN, but also via diffusible signals. Still, the routes by which diffusible signals from the SCN act, and whether and how this signaling modality is regulated, remains to be determined. Almost 90 years after the discovery of thehypothalamic-pituitary portal system, considered the sole brain portal system in the brain, we identified a new portal system connecting the SCN and a cirumventricular organum, the organum vascullosum of the lamina terminalis (OVLT) in mouse. This novel portal system, named hereSCN-OVLTP, stands as a likely candidate vascular route by which small amounts of biologically significant secretions generated in the SCN could reach specialized local targets in the OVLT. Because the OVLT provides the portal system with direct access to the CSF, this system can orchestrate rhythms throughout the body. For this to be proven however, fundamental properties of the SCN-OVLTP, including directionality of blood flow and underlying regulatory mechanisms must be determined. To address this critical gap in our knowledge, we first asked whether the SCN-OVLTp pathway occurs in rats as we showed for mice. Using iDisco clearing and high resolution light sheet microcopy our exciting preliminary data indicates that the SCN-OVLTP is in fact present in the rat. The OVLT, like the SCN is a heterogeneous structure, and it will be critical to assess which OVLT compartments are target of signals carried in the portal pathway. Importantly, we developed a novel surgical/imaging experimental approach that enables, for the first time, the in vivo assessment of blood flow and its regulation in the SCN-OVLTp. We determined that blood flows unidirectionally from the SCN towards the OVLT and notably, it varies according to the day-night cycle. In addition, we show that systemic vasopressin (VP) can access and travel within this portal system. Collectively, these data lead us to propose the overarching novel hypothesis that the SCN-OVLTP is a functionally relevant route by which low amounts of signals generated within the SCN can act in a diffusible manner to efficiently regulate distant targets via de CSF The proposed work will delineate (1) where the portal vessels originate within the SCN, and the targets reached by SCN-OVLTp within this CVO and its fenestrated blood veesels, and thence to the CSF; and (2) whether blood flow within the SCN-OVLTP is regulated in an activity-dependent manner, by photic stimulation and/or by systemic homeostatic challenges. Using a multidisciplinary approach and state-of-the-art techniques in Aim 1 we will characterize the SCN-OVLTP in the rat to determine the origin of the portal vessels within the SCN and their targets in the OVLT. In Aim 2, we will define whether blood flow directionality and velocity within SCN- OVLTP is amenable to regulation. We expect results from this work to contribute to a better understanding of fundamental mechanisms by which the SCN orchestrates circadian rhythmicity throughout the body. 1