Salt Intake Behavior Research Articles

Sodium-level-sensitive Sodium Channel and Salt-Intake Behavior

Mammals feel thirsty or develop an appetite for salt when the correct balance between water and sodium in the body fluid has been disrupted, but little is known about the mechanism in the brain that controls salt homeostasis. It has been postulated that the existence of both an osmoreceptor and a specific sodium receptor is required to accommodate the experimental data (Johnson and Edwards, 1990; Denton et al., 1996). Several candidate osmoreceptors have been reported (Oliet and Bourque, 1993; Wells, 1998; Liedtke et al., 2000); however, a specific sodium receptor has not been identified. The Nax channel—formerly called NaG/SCL11 (in rats), Nav2.3 (in mice) and Nav2.1 (in humans)—has been classified as a subfamily of voltage-gated sodium channels (Goldin et al., 2000). The primary structure of Nax, however, markedly differs from that of other voltage-gated sodium channel family members and includes differences in the key regions for voltage sensing and inactivation. The functional properties of the channel are poorly understood, as all attempts to induce functional expression of Nax in heterologous systems have failed. Several years ago, we generated mice in which the Nax gene was knocked-out by insertion of the lacZ gene in-frame and found that the Nax channel is expressed in cells in the circumventricular organs (CVOs) (Watanabe et al., 2000), in particular the subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT), which are important regions for the control of body fluid ionic balance; for the expression other than the CNS (see Watanabe et al., 2002). Under thirst conditions, Nax-deficient mice showed hyperactivity of the neurons in these two areas and ingested excessive salt: Wild-type mice take water and stop salt ingestion under dehydrated condition. Infusion of a hypertonic Na solution into the cerebral ventricle also induced extensive water intake and aversion to saline (0.3 M

The Subfornical Organ is the Primary Locus of Sodium-Level Sensing by NaxSodium 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 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.

Special Lecture 2: Brain function for the regulation of salt-Intake behavior

Special Lecture 2: Brain function for the regulation of salt-Intake behavior

A comparison of voluntary salt-intake behavior in Na x-gene deficient and wild-type mice with reference to peripheral taste inputs

The Na x channel, a subfamily of voltage-gated sodium channels, is thought to be a specific sodium receptor in the central nervous system. Our previous study revealed that Na x -gene-deficient mice consumed excessive amounts of NaCl even under water-deprived conditions. In the present study, to investigate whether the peripheral taste inputs are involved in the abnormal intake of salt in Na x -deficient mice ( homo), voluntary intake of various taste solutions in homo and wild-type mice ( wild) was examined under non-deprived conditions. Homo showed a higher preference for 0.15 M NaCl solution than wild. Preference ratios for other basic tastants were identical between groups. Transection of the chorda tympani (CT) or the glossopharyngeal (GP) nerve had little effect on salt-intake behavior in homo and wild. Although combined transection of the superior laryngeal (SL) and GP nerves decreased NaCl intake in homo but not in wild, there were no differences in preference ratios for NaCl in homo before and after SL+GP transection. On the other hand, preference ratios for NaCl in wild tended to increase after combined SL and GP transection. Consequently, preference ratios for NaCl after SL+GP transection were no different between homo and wild. While electrophysiological responses of the CT and the GP to various taste solutions were indistinguishable between homo and wild, those of the SL to NaCl in homo were smaller than those in wild only at lower concentrations (0.01 and 0.03 M). Thus, chemosensory inputs from the oro-pharyngeal regions had little effect on abnormal salt intake in homo, if any. From these results, it is suggested that the higher preference for NaCl in homo is mainly due to the lack of Na x channels in the central nervous system.

塩分摂取行動の制御は脳弓下器官のNa_xナトリウムチャンネルが担う

塩分摂取行動の制御は脳弓下器官のNa_xナトリウムチャンネルが担う

New Perspectives on the Structure and Function of the Na+ Channel Multigene Family

Recent studies on the voltage-gated Na+ channel (VGSC) have revealed several excellent discoveries regarding its structure and function. This article summarizes recent findings on VGSCs, and presents our views on the subject. Based on the multi-pore 3D model of the VGSC, we propose a ”twist-sprinkler“ model: (i) twisting and untwisting of the central cavity corresponds to the closed and open states of the channel, and (ii) cytoplasmic outlet pores sprinkle Na+ ions laterally over the inner surface of the plasma membrane to effect a rapid depolarization. VGSCs can be classified into two major categories. Category-I isoforms currently comprise nine highly homologous clones (Nav1.1- Nav1.9), most of which have been functionally expressed. In contrast, the category-II isoform consists of one clone (Nax), which has not been successfully expressed in an exogenous system. It is considerably different from the category-I isoforms, especially in the S4 segment, and shows little voltage dependence. The main function of the category-I isoforms is to form an action potential upstroke. However, NaV1.6 can also influence subthreshold electrical activity in neurons through the ”persistent“ and ”resurgent“ Na+ currents, indicating that the VGSC itself can modulate overall neuronal firing behavior. NaV1.8 and NaV1.9 are preferentially expressed in peripheral nociceptive neurons and contain a structure common to tetrodotoxin (TTX)-resistant Na+ channels. Both Nav1.8 and Nav1.9 play a pivotal role in pain sensation. The category-II isoform Nax (x = unknown function) is a ”concentration-sensitive“ but not ”voltage-sensitive“ Na+ channel. It is involved in regulation of salt intake behavior by sensing an increase in [Na+]o, and it should be renamed as Nac (c = concentration). Keywords: Na Channel, Multigene Family, INFLAMMATORY PAIN

The effect of amiloride on operantly conditioned performance in an NaCl taste detection task and NaCl preference in C57BL/6J mice.

A 2-response operant taste discrimination procedure, modified to assess taste sensitivity in water-restricted C57BL/6J mice, revealed a detection threshold of 0.065 M sodium chloride. Amiloride increased the threshold by approximately 1 log10 unit. These results are the first to demonstrate the necessity of the amiloride-sensitive taste transduction pathway in the normal detection of low concentrations of sodium chloride in mice and provide a functional context in which to evaluate electrophysiological findings. Two-bottle preference tests performed with these mice and additional naive mice revealed only marginal, if any, effects of amiloride on salt intake behavior, highlighting the importance of considering the relative attributes and limitations of different behavioral assays of taste function.

The effect of amiloride on operantly conditioned performance in an NaCl taste detection task and NaCl preference in C57BL/6J mice.

A 2-response operant taste discrimination procedure, modified to assess taste sensitivity in water-restricted C57BL/6J mice, revealed a detection threshold of 0.065 M sodium chloride. Amiloride increased the threshold by approximately 1 log10 unit. These results are the first to demonstrate the necessity of the amiloride-sensitive taste transduction pathway in the normal detection of low concentrations of sodium chloride in mice and provide a functional context in which to evaluate electrophysiological findings. Two-bottle preference tests performed with these mice and additional naive mice revealed only marginal, if any, effects of amiloride on salt intake behavior, highlighting the importance of considering the relative attributes and limitations of different behavioral assays of taste function.

Nav2/NaG Channel Is Involved in Control of Salt-Intake Behavior in the CNS

Na(v)2/NaG is a putative sodium channel, whose physiological role has long been an enigma. We generated Na(v)2 gene-deficient mice by inserting the lacZ gene. Analysis of the targeted mice allowed us to identify Na(v)2-producing cells by examining the lacZ expression. Besides in the lung, heart, dorsal root ganglia, and Schwann cells in the peripheral nervous system, Na(v)2 was expressed in neurons and ependymal cells in restricted areas of the CNS, particularly in the circumventricular organs, which are involved in body-fluid homeostasis. Under water-depleted conditions, c-fos expression was markedly elevated in neurons in the subfornical organ and organum vasculosum laminae terminalis compared with wild-type animals, suggesting a hyperactive state in the Na(v)2-null mice. Moreover, the null mutants showed abnormal intakes of hypertonic saline under both water- and salt-depleted conditions. These findings suggest that the Na(v)2 channel plays an important role in the central sensing of body-fluid sodium level and regulation of salt intake behavior.

Nav2/NaG channel is involved in control of salt intake behavior in the central nervous system

Nav2/NaG channel is involved in control of salt intake behavior in the central nervous system

Deficits in NaCl ingestion after damage to the central nucleus of the amygdala in the rat

These studies examined the NaCl intake behaviors of rats with bilateral electrolytic lesions of the central nucleus of the amygdala (CeAX). Daily need-free intake of 3% NaCl was abolished by CeAX even in rats in which it had been enhanced preoperatively by a history of repeated sodium depletions but was slightly restored by three successive postoperative sodium depletions. CeAX rats drank water but not 3% NaCl to high doses of DOCA and to the activation of cerebral angiotensin II, and expressed small but reliable salt intake (need-induced salt intake or salt appetite) after postoperative sodium depletions. Other ingestive behaviors (water drinking, intake of food and 5% sucrose) were normal. When given decreasing concentrations of NaCl solution the CeAX rats rejected them until the concentration reached 0.2%. These findings suggest that lesions to the central nucleus of the amygdala produce a global impairment in salt intake behaviors that is possibly due to an alteration in the central processing of the salt taste signal.

Regulation of water intake.

Regulation of water intake.