The subfornical organ is the primary locus of sodium-level sensing by Nax sodium channels for the control of salt-intake behavior

Dehydration causes an increase in the sodium (Na) concentration and osmolarity of body fluid. For Na homeostasis of the body, controls of Na and water intake and excretion are of prime importance. However, the system for sensing the Na level within the brain that is responsible for the control of Na- and water-intake behavior remains to be elucidated. We reported previously that the Na-x channel is preferentially expressed in the circumventricular organs (CVOs) in the brain and that Na-x knock-out mice ingest saline in excess under dehydrated conditions. Subsequently, we demonstrated that Na-x is a Na-level-sensitive Na channel. Here we show that the subfornical organ (SFO) is the principal site for the control of salt-intake behavior, where the Na-x channel is the Na- level sensor. Infusion of a hypertonic Na solution into the cerebral ventricle induced extensive water intake and aversion to saline in wild-type animals but not in the knock-out mice. Importantly, the aversion to salt was not induced by the infusion of a hyperosmotic mannitol solution with physiological Na concentration in either genotype of mice. When Nax cDNA was introduced into the brain of the knock-out mice with an adenoviral expression vector, only animals that received a transduction of the Na-x gene into the SFO among the CVOs recovered salt-avoiding behavior under dehydrated conditions. These results clearly show that the SFO is the center of the control of salt-intake behavior in the brain, where the Na- level-sensitive Na-x channel is involved in sensing the physiological increase in the Na level of body fluids.