D. A. Denton

Sensors for antidiuresis and thirst—osmoreceptors or CSF sodium detectors?

Change in sodium concentration of lateral ventricle CSF caused by intracarotid infusion of hypertonic solutions was measured in conscious sheep. Intracarotid infusion (1.6 ml/min) of 1 M NaCl, 2 M sucrose or 4.6 M or 2 M urea caused progressive increase of CSF sodium concentration, whereas 2 M glucose, 2 M galactose or 0.15 M NaCl did not. Of these solutions, only intracarotid 1 M NaCl or 2 M sucrose caused rapid water intake or rapid decrease in free water clearance. 2 M urea caused relatively slow antidiuresis and no water intake. 4.6 M urea which produced the largest rise of CSF[Na] caused slow antidiuresis and inconsistent small water intake. Infusion into a lateral ventricle (0.05 ml/min) of 0.35 M NaCl or 0.7 M sucrose, or fructose, made up in artificial CSF (0.15 M Na) or 0.5 M NaCl alone, all rapidly elicited an antidiuresis and water drinking, whereas intraventricular infusion of pure non-saline 1 M sucrose of 0.7 M urea in CSF was ineffective. Intraventricular 0.35 M NaCl in CSF caused greater antidiuretic and dipsogenic effects than intraventricular 0.7 M sucrose or fructose in CSF. It is postulated that a dual osmoreceptor-sodium sensor system may participate in regulating antidiuretic hormone secretion and thirst, and that the osmoreceptor system mediates the rapid antidiuresis and water drinking caused by intracarotid 1 M NaCl or 2 M sucrose, and is probably located in a brain region without a blood-brain barrier.

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE−/−) and compared with wild-type littermates. Compared with wild-type littermates, ACE−/− mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE−/− mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE−/− mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE−/− mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Prolonged intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse.

The effects of prolonged intracerebroventricular (i.c.v.) steroid infusions on memory performances (Y-maze arm discrimination test) and on neurosteroids brain levels were studied in young adult male mice. The Y-maze test consisted of two trials separated by a time interval. In the first trial, one arm of the maze (subsequently called novel arm) was closed, and mice were allowed to visit the two accessible arms. After a short 2-h intertrial interval (ITI), control mice explored preferentially the novel arm, whereas with a longer 6-h ITI, they did not remember the location of the novel arm and performed at random level (33% of time spent in each arm). Using a 2-h ITI, allopregnanolone (THPROG, 0.5 and 1 ng/h) decreased memory performances to random level after 3 and 6 days of infusion. Conversely, with a 6-h ITI, pregnenolone sulfate (PREG S, 10, 50, and 100 ng/h) significantly increased memory performances after 3 days, but only the smallest dose was still effective after 6 days. THPROG infusion (1 ng/h) increased the forebrain concentration of 5alpha-dihydroprogesterone (DHPROG) and tended to increase its own level. PREG S administration (10 ng/h) increased its own concentration and tended to increase those of pregnenolone (PREG) and of further metabolites. In conclusion, the memory-enhancing effects of PREG S and the inhibitory ones of THPROG have been confirmed. A persistent, however moderate, increase of PREG S brain concentration might be of interest for the treatment of amnesic deficits.

Change in Salt Intake Affects Blood Pressure of Chimpanzees. Implications for Human Populations

Background— Addition of up to 15.0 g/d salt to the diet of chimpanzees caused large rises in blood pressure, which reversed when the added salt was removed. Effects of more modest alterations to sodium intakes in chimpanzees, akin to current efforts to lower sodium intakes in the human population, are unknown. Methods and Results— Sodium intakes were altered among 17 chimpanzees in Franceville, Gabon, and 110 chimpanzees in Bastrop, Tex. In Gabon, chimpanzees had a biscuit diet of constant nutrient composition except that the sodium content was changed episodically over 3 years from 75 to 35 to 120 mmol/d. In Bastrop, animals were divided into 2 groups; 1 group continued on the standard diet of 250 mmol/d sodium for 2 years, and sodium intake was halved for the other group. Lower sodium intake was associated with lower systolic, diastolic, and mean arterial blood pressures in Gabon (2-tailed P<0.001, unadjusted and adjusted for age, sex, and baseline weight) and Bastrop (P<0.01, unadjusted; P=0.08 to 0.10, adjusted), with no threshold down to 35 mmol/d sodium. For systolic pressure, estimates were −12.7 mm Hg (95% confidence interval, −16.9 to −8.5, adjusted) per 100 mmol/d lower sodium in Gabon and −10.9 mm Hg (95% confidence interval, −18.9 to −2.9, unadjusted) and −5.7 mm Hg (95% confidence interval, −12.2 to 0.7, adjusted) for sodium intake lower by 122 mmol/d in Bastrop. Baseline systolic pressures higher by 10 mm Hg were associated with larger falls in systolic pressure by 4.3/2.9 mm Hg in Gabon/Bastrop per 100 mmol/d lower sodium. Conclusions— These findings from an essentially single-variable experiment in the species closest to Homo sapiens with high intakes of calcium and potassium support intensified public health efforts to lower sodium intake in the human population.

Subfornical organ lesion decreases sodium appetite in the sodium-depleted rat.

The effect of subfornical organ (SFO) lesion on various models of ingestive behaviour was investigated in rats. Intake of water after 24 h water deprivation or systemic administration of hypertonic NaCl were not altered by SFO lesions. Intake of food or water after 24 h of food deprivation were not altered by SFO lesions. Intake of NaCl after furosemide-induced Na depletion was decreased by ablation of the SFO. This decrease in Na intake was ameliorated by pretreatment with a low dose of captopril. These results suggest that the SFO is involved in Na intake after Na depletion, but not in water or food intake following periods of water or food deprivation, respectively. The observation that a low dose of captopril can eliminate the decrease in Na appetite which occurred subsequent to SFO lesion suggests that other brain areas may also participate in Na-depletion-induced Na appetite.

Neural correlates of the emergence of consciousness of thirst

Thirst was induced by rapid i.v. infusion of hypertonic saline (0.51 M at 13.4 ml/min). Ten humans were neuroimaged by positron-emission tomography (PET) and four by functional MRI (fMRI). PET images were made 25 min after beginning infusion, when the sensation of thirst began to enter the stream of consciousness. The fMRI images were made when the maximum rate of increase of thirst occurred. The PET results showed regional cerebral blood flow changes similar to those delineated when thirst was maximal. These loci involved the phylogenetically ancient areas of the brain. fMRI showed activation in the anterior wall of the third ventricle, an area that is key in the genesis of thirst but is not an area revealed by PET imaging. Thus, this region plays as major a role in thirst for humans as for animals. Strong activations in the brain with fMRI included the anterior cingulate, parahippocampal gyrus, inferior and middle frontal gyri, insula, and cerebellum. When the subjects drank water to satiation, thirst declined immediately to baseline. A precipitate decline in intensity of activation signal occurred in the anterior cingulate area (Brodmann area 32) putatively related to consciousness of thirst. The intensity of activation in the anterior wall of the third ventricle was essentially unchanged, which is consistent with the fact that a significant time (15–20 min) would be needed before plasma Na concentration changed as a result of water absorption from the gut.

Osmoregulatory thirst in sheep is disrupted by ablation of the anterior wall of the optic recess

Ablation of the organum vasculosum of the lamina terminalis (OVLT) and adjacent midline tissue in the anterior wall of the optic recess of the third ventricle resulted in greatly reduced water drinking to intracarotid infusion of hypertonic NaCl in sheep. Daily food and water intake and angiotensin II drinking were not consistently reduced by these lesions. Tissue in or close to the OVLT is probably involved in osmotically induced water-drinking.

Circulating relaxin acts on subfornical organ neurons to stimulate water drinking in the rat

Relaxin, a peptide hormone secreted by the corpus luteum during pregnancy, exerts actions on reproductive tissues such as the pubic symphysis, uterus, and cervix. It may also influence body fluid balance by actions on the brain to stimulate thirst and vasopressin secretion. We mapped the sites in the brain that are activated by i.v. infusion of a dipsogenic dose of relaxin (25 μg/h) by immunohistochemically detecting Fos expression. Relaxin administration resulted in increased Fos expression in the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus, and magnocellular neurons in the supraoptic and paraventricular nuclei. Ablation of the SFO abolished relaxin-induced water drinking, but did not prevent increased Fos expression in the OVLT, supraoptic or paraventricular nuclei. Although ablation of the OVLT did not inhibit relaxin-induced drinking, it did cause a large reduction in Fos expression in the supraoptic nucleus and posterior magnocellular subdivision of the paraventricular nucleus. In vitro single-unit recording of electrical activity of neurons in isolated slices of the SFO showed that relaxin (10−7 M) added to the perfusion medium caused marked and prolonged increase in neuronal activity. Most of these neurons also responded to 10−7 M angiotensin II. The data indicate that blood-borne relaxin can directly stimulate neurons in the SFO to initiate water drinking. It is likely that circulating relaxin also stimulates neurons in the OVLT that influence vasopressin secretion. These two circumventricular organs that lack a blood–brain barrier may have regulatory influences on fluid balance during pregnancy in rats.

Physiological and pathophysiological influences on thirst.

Thirst motivates animals to seek fluid and drink it. It is regulated by the central nervous system and arises from neural and chemical signals from the periphery interacting in the brain to stimulate a drive to drink. Our research has focussed on the lamina terminalis and the manner in which osmotic and hormonal stimuli from the circulation are detected by neurons in this region and how that information is integrated with other neural signals to generate thirst. Our studies of osmoregulatory drinking in the sheep and rat have produced evidence that osmoreceptors for thirst exist in the dorsal cap of the organum vasculosum of the lamina terminalis (OVLT) and in the periphery of the subfornical organ, and possibly also in the median preoptic nucleus. In the rat, the hormones angiotensin II and relaxin act on neurons in the periphery of the subfornical organ to stimulate drinking. Studies of human thirst using functional magnetic resonance imaging (fMRI) techniques show that systemic hypertonicity activates the lamina terminalis and the anterior cingulate cortex, but the neural circuitry that connects sensors in the lamina terminalis to cortical regions subserving thirst remains to be determined. Regarding pathophysiological influences on thirst mechanisms, both excessive (polydipsia) and inadequate (hypodisia) water intake may have dire consequences. One of the most common primary polydipsias is that observed in some cases of schizophrenia. The neural mechanisms causing the excessive water intake in this disorder are unknown, so too are the factors that result in impaired thirst and inadequate fluid intake in some elderly humans.

The role of primordial emotions in the evolutionary origin of consciousness

Primordial emotions are the subjective element of the instincts which are the genetically programmed behaviour patterns which contrive homeostasis. They include thirst, hunger for air, hunger for food, pain and hunger for specific minerals etc. There are two constituents of a primordial emotion--the specific sensation which when severe may be imperious, and the compelling intention for gratification by a consummatory act. They may dominate the stream of consciousness, and can have plenipotentiary power over behaviour. It is hypothesized that early in animal evolution complex reflex mechanisms in the basal brain subserving homeostatic responses, in concert with elements of the reticular activating system subserving arousal, melded functionally with regions embodied in the progressive rostral development of the telencephalon. This included the emergent limbic and paralimbic areas, and the insula. This phylogenetically ancient organization subserved the origin of consciousness as the primordial emotion, which signalled that the organisms existence was immediately threatened. Neuroimaging confirms major activations in regions of the basal brain during primordial emotions in humans. The behaviour of decorticate humans and animals is discussed in relation to the possible existence of primitive awareness. Neuroimaging of the primordial emotions reveals that rapid gratification of intention by a consummatory act such as ingestion causes precipitate decline of both the initiating sensation and the intention. There is contemporaneous rapid disappearance of particular regions of brain activation which suggests they may be part of the jointly sufficient and severally necessary activations and deactivations which correlate with consciousness [Crick, F. & Koch, C. (2003). A framework for consciousness. NatureNeuroscience,6, 119-126].