Discovery of a Second Venous Portal System in the Mammalian Brain

Yao Y, Taub AB, LeSauter J, Silver R. Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain. Nat Commun 2021;12(1):5643. doi: 10.1038/s41467-021-25793-z.

Background: The suprachiasmatic nucleus (SCN) of the hypothalamus acts as the brain’s circadian clock, coordinating daily physiological rhythms. While the pituitary portal system has been the only known vascular portal pathway in the mammalian brain, the mechanisms by which SCN neurosecretions reach their targets remained unclear. Understanding whether specialized vascular routes exist for SCN signaling could reveal novel modes of brain communication.

Hypothesis: This study hypothesized that a portal vascular system links the SCN to a nearby circumventricular organ, the organum vasculosum of the lamina terminalis (OVLT), allowing efficient transfer of SCN-derived humoral signals without dilution in systemic circulation.

Methods: The authors examined adult mouse brains using tissue clearing with an iDISCO protocol, triple-label immunostaining for arginine vasopressin, collagen and smooth muscle actin, and light-sheet microscopy. Three-dimensional image processing and tracing of capillary networks were performed using Imaris and Vesselucida 360, with quantitative vascular analyses carried out in Vesselucida Explorer.

Results: High-resolution imaging revealed continuous portal capillaries connecting the rostral tip of the SCN to the ventral superficial plexus of the OVLT, coursing along the floor of the third ventricle. The SCN shell exhibited a significantly denser and more complex vasculature than the core (8.7 × 10^-6 vs. 4.6 × 10^-6 nodes/µm³, p < 0.001). These vessels were distinct from lateral hypothalamic veins and comparable in structure to the hypophyseal portal system.

Conclusions: The findings identify a second venous portal system in the mammalian brain connecting the SCN and OVLT, suggesting a direct vascular route for circadian signals and redefining pathways of neurovascular communication.