Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor

Abstract

Kinsman B, Cowles J, Lay J, Simmonds SS, Browning KN, Stocker SD. Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor. Recent studies suggest the ability of the central nervous system to detect changes in osmolality is mediated by products of the genes encoding the transient receptor potential vanilloid-1 (TRPV1) or vanilloid-4 (TRPV4) channel. The purpose of the present study was to determine whether deletion of TRPV1 and/or TRPV4 channels altered thirst responses to cellular dehydration in mice. Injection of 0.5 or 1.0 M NaCl produced dose-dependent increases in cumulative water intakes of wild-type (WT), TRPV1 Ϫ/Ϫ , TRPV4 Ϫ/Ϫ , and TRPV1 Ϫ/Ϫ V4 Ϫ/Ϫ mice. However, there were no differences in cumulative water intakes between WT versus any other strain despite similar increases in plasma electrolytes and osmolality. Similar results were observed after injection of hypertonic mannitol. This was a consistent finding regardless of the injection route (intraperitoneal vs. subcutaneous) or timed access to water (delayed vs. immediate). There were also no differences in cumulative intakes across strains after injection of 0.15 M NaCl or during a time-controlled period (no injection). Chronic hypernatremia produced by sole access to 2% NaCl for 48 h also produced similar increases in water intake across strains. In a final set of experiments, subcutaneous injection of 0.5 M NaCl produced similar increases in the number of Fos-positive nuclei within the organum vasculosum of the lamina terminalis and median preoptic nucleus across strains but significantly smaller number in the subfornical organ of WT versus TRPV1 Ϫ/Ϫ V4 Ϫ/Ϫ mice. Collectively, these findings suggest that TRPV1 and/or TRPV4 channels are not the primary mechanism by which the central nervous system responds to cellular dehydration during hypernatremia or hyperosmolality to increase thirst. hypernatremia; water intake; organum vasculosum of the lamina terminalis; subfornical organ; cellular dehydration THE CENTRAL NERVOUS SYSTEM plays a pivotal role in body fluid homeostasis through its ability to sense changes in osmotic pressure and subsequently alter fluid intake, secretion of antidiuretic hormone, natriuresis, and sympathetic nerve activity (5,19,30,42,45,50). Physiologically, changes in extracellular osmotic pressure are typically the result of changes in the extracellular concentration of Na ϩ and/or Cl Ϫ to produce cellular dehydration. The most influential set of osmosensitive neurons is located within the forebrain lamina terminalis (5). This region of the brain contains several structures including two circumventricular organs: the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO). A number of laboratories have demonstrated that acute or chronic hypernatremia increases Fos immunoreactivity in the OVLT and SFO (21,36,40,46). Second, in vivo and in vitro electrophysiological studies have reported that acute hypernatremia or hyperosmolality i...

Nax signaling evoked by an increase in [Na+] in CSF induces water intake via EET-mediated TRPV4 activation

“…No genotypic differences were observed in water intake. The negative experimental results of TRPV1-KO and TRPV4-KO mice were consistent with those reported by Stocker's group for TRPV1 and TRPV4 (23,49) and by Suzuki's group for TRPV4 (36).…”

“…1), as was partly reported by other groups (23,36,49). However, after the intracerebroventricular injection of a hypertonic NaCl aCSF, water intake by TRPV4-KO and Na x -KO mice was clearly abnormal (Fig.…”

“…They also showed that water intake after the intraperitoneal injection of a hypertonic solution was significantly less in TRPV1-KO mice than in wild-type (WT) mice (Ͻ15%) (14). However, Stocker's group (23,49) reported that TRPV1-KO mice displayed normal thirst responses and the central induction of Fos, a marker of neuronal activation, under systemic hypertonic conditions such as a subcutaneous injection of hypertonic saline, water deprivation, and sole access to a salt solution. TRPV4 was originally considered to detect extracellular hypotonicity (25).…”

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

“…Ninety minutes later, mice were deeply anesthetized with isoflurane (3% in 100% O 2 ) and perfused transcardially with isotonic saline and 4% paraformaldehyde. Brains were postfixed overnight at 4°C, sectioned at 30 m with a vibratome, and processed immunocytochemically for Fos protein (Kinsman et al 2014;Taylor et al 2008) and/or hemagglutinin (HA)-Tag to assess DREADD expression. Sections were incubated in a rabbit anti-cFos antibody (1:4,000; EMD Biosciences Ab5-PC38) at 4°C for 48 h and subsequently visualized with an Alexa Fluor 594 goat anti-rabbit antibody (1:250; Molecular Probes).…”

“…Neurons in these regions lack a complete blood-brain barrier and therefore can readily detect changes in circulating substances that other brain regions cannot (McKinley et al 2003). For example, studies using in vivo single-unit recordings (Gutman et al 1988;Tanaka et al 1985) or immunocytochemical localization of Fos (Kinsman et al 2014;Larsen and Mikkelsen 1995;Oldfield et al 1994;Taylor et al 2008) indicate that SFO neurons are responsive to either NaCl or the peptide hormone angiotensin II (ANG II). Activation of SFO neurons increases water intake Routtenberg 1973, 1978;Smith et al 1995), plasma vasopressin levels (Ferguson and Kasting 1986), and arterial blood pressure (Gutman et al 1985).…”