Global Clock Coordination by the Brain Clock in the Suprachiasmatic Nucleus Through Relay and Amplification of Diffusible and Neural Signaling

The brain clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus receives direct retinal input, thereby providing the entire body with an internal representation of external solar time. The pathways by which this small nucleus signals so broadly involve co-occurring nervous and diffusible output signals, although the latter are less understood. Portal pathways, such as the well-known pituitary portal pathway, provide a mechanism, whereby signals of neural origin can reach local, specialized targets without suffering dilution in the systemic blood supply. Newly discovered vascular pathways involve direct connections between each of the sensory circumventricular nuclei at its point of attachment to the brain. These nuclei line the brain's ventricles, and their leaky blood vessels and large perivascular spaces represent a route, whereby secretions from the SCN can be relayed and then amplified, providing a pathway to achieve global coordination of circadian clock signaling. This review provides a narrative that incorporates our understanding of SCN neural and diffusible output signals, with particular emphasis on the contribution of brain fluidic compartments and the fluids therein.