Trends in Neurosciences
Volume 36, Issue 11, November 2013, Pages 661-673
Journal home page for Trends in Neurosciences

Review
Central regulation of body-fluid homeostasis

https://doi.org/10.1016/j.tins.2013.08.004Get rights and content

Highlights

  • We review recent progress in the identification of brain sensors to monitor body-fluid conditions.

  • The Na-level sensor, Nax, is expressed in glial cells in the circumventricular organs.

  • Some promising candidates for osmosensors have been postulated, but not yet concluded.

Body-fluid homeostasis is essential to life, and the concentration of Na+ ([Na+]) and osmolality in plasma and the cerebrospinal fluid (CSF) are continuously monitored in the brain. To maintain a physiological level of Na/osmolality in body fluids, the control of Na and water intake and excretion are of prime importance. Two independent sensing systems for [Na+] and osmolality in circumventricular organs (CVOs) have long been postulated to be involved in the monitoring of body-fluid conditions. In the past decade, several molecules were reported as promising candidates for these sensors – Nax for the [Na+] sensor and transient receptor potential (TRP) channels for the osmosensor. This review presents a summary of developments in these areas over recent years.

Introduction

Mammals have a set of homeostatic mechanisms that work together to maintain body-fluid osmolality at approximately 300 mOsm/kg largely through the intake or excretion of water and salt 1, 2. This homeostatic osmoregulation is vital because changes in cell volume caused by severe hypertonicity or hypotonicity can lead to irreversible damage to organs and cause lethal neurological trauma 3, 4, 5. Sodium (Na) is a major electrolyte in extracellular fluids and the main determinant of osmolality. When animals are dehydrated, [Na+] in body fluids increases, together with osmolality.

Animals exhibit several prominent and effective responses to dehydration; for example, behavioral responses such as water intake and Na aversion, and the control of kidney functions for water retention. Renal water retention is mediated by vasopressin (VP), which is synthesized by magnocellular neurons in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, and are released into the blood at the posterior lobe of the pituitary gland 6, 7. Increases in plasma osmolality of a few percent are sufficient to induce the secretion of VP [8].

Earlier studies demonstrated that intracarotid infusions of hypertonic solutions of NaCl or sucrose, but not urea, resulted in antidiuresis 9, 10, 11, 12. Because urea is permeable to cell membranes, these findings suggested that cellular dehydration (cell shrinking) stimulated by hyperosmolality is required for VP release. McKinley et al. reported that an injection of hypertonic NaCl solution into the 3rd ventricle of conscious sheep caused greater antidiuretic and drinking responses than that of equiosmolar hypertonic sucrose solution 13, 14. Thus, both a Na-level sensor and osmosensor have been proposed to be present in the brain (see Figure IA in Box 1). Furthermore, NaCl, sucrose, and urea hardly permeate across the blood–brain barrier. Therefore, these findings also suggest that the sensing cells are located at brain regions devoid of a blood–brain barrier, such as sensory circumventricular organs (sCVOs) 14, 15.

This was supported by immunohistochemical studies on water-deprived animals, in that the expression of activity-dependent immediate-early genes such as c-Fos was increased in the two sCVOs, the subfornical organ (SFO), and organum vasculosum of the lamina terminalis (OVLT), in addition to the median preoptic nucleus (MnPO), SON, and PVN 16, 17 (see Figure IB in Box 1). Neurons in the SFO, MnPO, and OVLT project to the SON 16, 18 and the PVN [19] directly or indirectly. An injection of hypertonic solutions into the 3rd ventricle was shown to provoke VP secretion and the drinking response 20, 21. The SFO, MnPO, and OVLT are located in the dorsal to ventral front wall of the 3rd ventricle (the lamina terminalis), and lesions in this area attenuated these responses to the systemic administration of hypertonic solutions 22, 23, 24, 25. Furthermore, functional magnetic resonance imaging (MRI) studies recently revealed that the anteroventral 3rd ventricle (A3V) region was activated during hypertonicity in animals [26] and humans [27]. These studies suggested that sensors for body-fluid conditions are present in these brain regions. In the past decade the identification of these sensors has made significant progress in our understanding of the processes for central regulation of body-fluid homeostasis.

We review here the Na-level sensor, identified by ourselves, and osmosensors, identified by others, in the brain. Nax (also known as SCN7A; sodium channel, voltage-gated, type VII; also NaG) channels specifically expressed in glial cells in the sCVOs sense changes in [Na+] in plasma and CSF, and the signal is transmitted from the glial cells to neurons via lactate in the SFO. The transient receptor potential (TRP) channels, including TRPV1 and TRPV4, expressed in neurons in the sCVOs are suggested to sense cell volume changes associated with the shift of extracellular osmolality. The signals sensed by these sensors in the sCVOs appear to assume vital roles in the control of salt/water intake and VP release.

Section snippets

Na-level sensor in the brain

As the major electrolyte of the extracellular fluid, Na plays a fundamental role in maintaining the volume and composition of every fluid compartment in the body [28]. Therefore, the amount of Na in body fluids must be tightly regulated to ensure the optimal performance of numerous physiological processes based on the ion concentration across cell membranes, including neuronal excitability, substance transport, glomerular filtration, and renal excretion of aqueous waste, and the control of

Osmosensors in the brain

Because the permeability of cell membranes is higher to water than to ions, an increase or decrease in extracellular osmolality leads to the shrinkage or swelling of cells. Water channels, aquaporins (AQPs), are considered to contribute to cellular shrinkage and swelling [49]. Earlier studies suggested that the mammalian brain detected systemic hypertonicity through a process involving cellular shrinkage. The shrinkage or swelling of cells leads to the deformation of cell morphology and lipid

Concluding remarks and future directions

Although major advances have been made during the past decade in understanding the central regulation of body-fluid homeostasis, many issues remain unresolved. As described above, while TRPV channels are promising candidates for osmosensors in the brain, further studies are needed to validate them. Studies using KO mice are controversial, which may suggest that additional osmosensors exist in the brain. Many candidates have been identified as osmosensors (mechanosensors) as described above.

The

Acknowledgments

We thank Takeshi Y. Hiyama for his critical reading of this manuscript and A. Kodama for her secretarial assistance. This work was supported by Grant-in-Aid for Scientific Research (S) (24220010) from JSPS (Japan Society for the Promotion of Science) to M.N.

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      Animals exhibit prominent and effective responses to water deprivation, including behavioral responses, such as the induction of water intake and aversion to sodium (Na), along with vasopressin (VP)-induced reductions in urine volumes (McKinley et al., 1974, 2003; Johnson, 2007). [Na+] is the main factor influencing osmolality in vivo, and is continuously monitored in the brain to be maintained within a physiological range (McKinley et al., 1978, 2003; Noda and Sakuta, 2013). Injection of hypertonic NaCl solution into the third ventricle causes greater antidiuretic and drinking responses than that of equiosmolar hypertonic sucrose solution in conscious sheep (McKinley et al., 1974, 1978) and mice (Sakuta et al., 2016).

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