Novel SCN-OVLT portal system: Dissecting Anatomical and Functional Properties - 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 organ, the organum vasculosum 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 cerebral spinal fluid (CSF), this system
can orchestrate rhythms throughout the body. For this to be proven, 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 targets of signals carried in the portal pathway. 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 that 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 the CSF.
The proposed work will delineate (1) where the portal vessels originate within the SCN, and the targets reached
by the portal vessels within the OVLT and its fenestrated blood vessels, 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.
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