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Link to original content: https://pubmed.ncbi.nlm.nih.gov/15496663/
The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior - PubMed Skip to main page content
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. 2004 Oct 20;24(42):9276-81.
doi: 10.1523/JNEUROSCI.2795-04.2004.

The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior

Takeshi Y Hiyama  1 , Eiji Watanabe, Haruo Okado, Masaharu Noda
Affiliations

The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior

Takeshi Y Hiyama et al. J Neurosci. .

Abstract

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 Na(x) 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.

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Figures

Figure 1.
Figure 1.
Nax knock-out mice exhibit abnormal salt-intake behavior under dehydrated conditions. A, Preference-aversion function for various saline concentrations. To avoid differences in the cumulative effect depending on the salt-intake history of mice, 10 mice were used freshly for each concentration (accordingly, a total of 70 mice for each genotype), and feeding was stopped for 12 hr during the test. *p < 0.01 by one-tailed Mann-Whitney tests; mean ± SE; n = 10. B, Averaged time course of water and saline (0.3 m NaCl) intake in wild-type (+/+) and knock-out (-/-) mice during the dark phase immediately after 48 hr dehydration. Each point shows the average quantity per 10 min period. n = 10. C, Preference ratio for the 0.3 m NaCl solution for 12 hr before and after 48 hr dehydration. The data were obtained with the volumes of water and saline consumed during the period of 12 hr. *p < 0.01 by one-tailed Mann-Whitney tests; mean ± SE; n = 10. D, Averaged time course of total intake of water and saline in wild-type (+/+) and knock-out (-/-) mice during 12 hr in the dark phase immediately after 48 hr dehydration. Each point shows the average of six mice for 10 min bins of data.
Figure 2.
Figure 2.
Nax knock-out mice are insensitive to increases of the Na level in the CSF. A, Top, Location of the cannula for intracerebroventricular microinfusions. The tip of the cannula was positioned at the lateral ventricle. Bottom, A schematic representation of the experimental setup for the two-bottle test. Two drinking tubes were presented to free-moving mice infused with sodium solutions into the cerebral ventricle for 12 hr. B, Averaged time course of water and saline (0.3 m NaCl) intake in wild-type (+/+) and knock-out (-/-) mice during intracerebroventricular infusions of a hypertonic (0.5 m) NaCl solution or hypertonic mannitol (0.145 m NaCl plus 0.71 m mannitol) solution. Each point shows the average quantity per 10 min period. n = 10. C, Preference ratio for the 0.3 m NaCl solution for 12 hr during intracerebroventricular infusions of test solutions. *p < 0.01 by one-tailed Mann-Whitney tests; mean ± SE; n = 10. D, Total intake volume for 12 hr during intracerebroventricular infusions of test solutions. Mean ± SE; n = 10.
Figure 3.
Figure 3.
Abnormal salt-intake behavior of Nax knock-out mice was rescued by introduction of the Nax gene to SFO. A, The location of the SFO and OVLT in a coronal section of the mouse brain. B, The coronal sections of the brain showing the loci infected by the expression of EGFP (left column). Time course of water and saline (0.3 m NaCl) intake by the infected mice before and after 48 hr dehydration (middle and right columns, respectively). Behavioral data are the average of six mice that were successfully infected in a specific site in the brain by an adenoviral vector encoding egfp (EGFP) or by vectors encoding Nax and egfp (Nax and EGFP). C, Preference ratio for the 0.3 m NaCl solution. *p < 0.01 by one-tailed Mann-Whitney test; mean ± SE; n = 6.
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