Activation Of Arginine Vasopressin Neurons Research Articles

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons.

SummaryMisfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.

Copulation or sensory cues from the female augment Fos expression in arginine vasopressin neurons of the posterodorsal medial amygdala of male rats.

BackgroundThe posterodorsal part of the medial amygdala is essential for processing reproductively salient sensory information in rodents. This is the initial brain structure where information from olfactory system and male hormones intersect. The neurochemical identity of the neurons participating in the sensory processing in medial amygdala remains presently undetermined. Many neurons in this brain structure express arginine vasopressin in a testosterone-dependent manner, suggesting that this neuropeptide is maintained by the androgenic milieu.MethodHere we use Fos, a protein expressed by recently active neurons, to quantify activation of arginine vasopressin neurons after exposure to odor from physically inaccessible female. We compare it to mating with accessible female and to reproductively innocuous odor.ResultsWe show that inaccessible female activate arginine vasopressin neurons in the male posterodorsal medial amygdala. The magnitude of activation is not further enhanced when physical access with resultant mating is granted, even though it remains undetermined if same population of AVP neurons is activated by both inaccessible female and copulation. We also show that arginine vasopressin activation cannot be fully accounted for by mere increase in the number of Fos and AVP neurons.ConclusionThese observations posit a role for the medial amygdala arginine vasopressin in reproductive behaviors, suggesting that these neurons serve as integrative node between the hormonal status of the animal and the availability of reproductive opportunities.

Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus

Familial neurohypophysial diabetes insipidus (FNDI) is a rare disease that is inherited in an autosomal dominant manner. In a previous study, we made a mouse model for FNDI, which showed progressive polyuria accompanied by inclusion bodies in the arginine vasopressin (AVP) neurons formed by aggregates in the endoplasmic reticulum. The present study was conducted to determine whether the activities of AVP neurons are related to the phenotype progression in the FNDI model. In the first experiment, female heterozygous mice were administered either desmopressin (dDAVP) or a vehicle (control) subcutaneously with osmotic minipumps for 30 days. The dDAVP treatment significantly decreased the urine volume, AVP mRNA expression, and inclusion bodies in the AVP neurons. Urine volume in the dDAVP group remained significantly less than the control for 14 days even after the minipumps were removed. In the second experiment, the males were fed either a 0.2% Na or 2.0% Na diet for 6 mo. Urine AVP excretion was significantly increased in the 2.0% Na group compared with the 0.2% Na group for the first 2 mo but gradually decreased thereafter. Throughout the experiments, urine volume increased progressively in the 2.0% Na group but not in the 0.2% Na group. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased in the 2.0% Na compared with the 0.2% Na group. These data demonstrated that activation of AVP neurons could accelerate the aggregate formation as well as the progression of the polyuria in the FNDI model mice.

The chemokine SDF-1/CXCL12 modulates the firing pattern of vasopressin neurons and counteracts induced vasopressin release through CXCR4

Chemokines play a key role in inflammation. They are expressed not only in neuroinflammatory conditions, but also constitutively by different cell types, including neurons in the normal brain, suggesting that they may act as modulators of neuronal functions. Here, we investigated a possible neuroendocrine role of the chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. We demonstrated the colocalization of SDF-1 and its receptor CXCR4 with arginine vasopressin (AVP) in the magnocellular neurons of the supraoptic nucleus (SON) and the paraventricular hypothalamic nucleus and on AVP projections to the neurohypophysis. Electrophysiological recordings of SON neurons demonstrated that SDF-1 affects the electrical activity of AVP neurons through CXCR4, resulting in changes in AVP release. We observed that SDF-1 can blunt the autoregulation of AVP release in vitro and counteract angiotensin II-induced plasma AVP release in vivo. Furthermore, a short-term physiological increase in AVP release induced by enhanced plasma osmolarity, which was produced by the administration of 1 M NaCl i.p., was similarly blocked by central injection of SDF-1 through CXCR4. A change in water balance by long-term salt loading induced a decrease in both SDF-1 and CXCR4 parallel to that of AVP immunostaining in SON. From these data, we demonstrate that chemokine actions in the brain are not restricted to inflammatory processes. We propose to add to the known autoregulation of AVP on its own neurons, a second autocrine system induced by SDF-1 able to modulate central AVP neuronal activity and release.

Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release.

Apelin, a recently isolated neuropeptide that is expressed in the supraoptic and the paraventricular nuclei, acts on specific receptors located on vasopressinergic neurons. The increased phasic pattern of these neurons facilitates sustained antidiuresis during dehydration or lactation. Here, we investigated whether apelin interacts with arginine vasopressin (AVP) to maintain body fluid homeostasis. We first characterized the predominant molecular forms of endogenous hypothalamic and plasma apelin as corresponding to apelin 13 and, to a lesser extent, to apelin 17. We then demonstrated that, in lactating rats, apelin was colocalized with AVP in supraoptic nucleus magnocellular neurons and given intracerebroventricularly inhibited the phasic electrical activity of AVP neurons. In lactating mice, intracerebroventricular administration of apelin 17 reduced plasma AVP levels and increased diuresis. Moreover, water deprivation, which increases systemic AVP release and causes depletion of hypothalamic AVP stores, decreased plasma apelin concentrations and induced hypothalamic accumulation of the peptide, indicating that AVP and apelin are conversely regulated to facilitate systemic AVP release and suppress diuresis. Opposite effects of AVP and apelin are likely to occur at the hypothalamic level through autocrine modulation of the phasic electrical activity of AVP neurons. Altogether, these data demonstrate that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. The coexistence of apelin and AVP in magnocellular neurons, their opposite biological effects, and regulation are likely to play a key role for maintaining body fluid homeostasis.

Effect of indomethacin on the c-fos expression in AVP and TH neurons in rat brain induced by lipopolysaccharide

The aim of the present study was to investigate the effect of indomethacin on the Fos expression in arginine vasopressin (AVP)-containing neurons in the hypothalamus and tyrosine hydroxylase (TH)-containing neurons in the locus coeruleus (LC) using dual-labeled immunohistochemistry. In the hypothalamus, intraperitoneal (i.p) injection of different doses [2.5 μg/100 g, 125 μg/100 g body weight (b.w.)] of lipopolysaccharide (LPS) induced a significant Fos expression in AVP neurons in the supraoptic nucleus (SON), the magnocellular division (mPVN) and the parvocellular division (pPVN) of the paraventricular nucleus (PVN). Pretreatment with the cyclooxygenase inhibitor indomethacin (0.8 mg/100 g b.w.) significantly blocked the Fos expression in these AVP neurons induced by a low dose of LPS (2.5 μg/100 g) but had no effect on the Fos expression induced by a high dose of LPS (125 μg/100 g). Similarly, in the brain stem, a large number of TH-positive neurons in the LC expressed Fos after administration of either dose of LPS. Indomethacin prevented the Fos expression induced only by a low dose of LPS, but not by a high dose of LPS. These results suggest that the activation of AVP neurons in PVN and SON and TH neurons in LC response to immune challenge might be mediated—at least partially—by prostaglandins.

Differential expression of estrogen receptor alpha and beta immunoreactivity in the human supraoptic nucleus in relation to sex and aging.

The dorsolateral supraoptic nucleus (dl-SON) is the main production site of plasma arginine vasopressin (AVP). Plasma AVP levels and the activity of AVP neurons in humans are higher in males than in premenopausal females. On the other hand, an increased activity of AVP neurons becomes prominent in postmenopausal women who have strongly decreased estrogen levels. As estrogens are presumed to inhibit AVP production in a receptor-mediated way, we studied estrogen receptor (ER) alpha and beta immunoreactivity in the dl-SON. Hypothalami of 34 controls were subdivided into 4 groups within a 50-yr boundary (young men, young women, elderly men, and elderly women). The AVP part of the dl-SON of young women contained 50 times more neurons with ERbeta nuclear staining than that in young men and 250 times more than that in elderly women. In addition, young women also showed more ERbeta cytoplasmic staining than young men and elderly women. In contrast to the ERbeta immunoreactivity, no differences were found in the number of ERalpha-positive neurons in the 4 groups, but the age and sex pattern of ERalpha staining was basically opposite that of ERbeta. Significant correlations between the percentage of ERbeta- and ERalpha-positive and -negative AVP neurons and age were found in women, but not in men. Our data demonstrate for the first time a strong decrease of ERbeta and an increase of ERalpha immunoreactivity in AVP neurons of the dl-SON of postmenopausal women. Both receptor changes are proposed to participate in the activation of the AVP neurons in postmenopausal women.

Circadian changes in arginine vasopressin level in the suprachiasmatic nuclei in the rat

Arginine vasopressin (AVP) neurons were preferentially localized in the dorsomedial part of the suprachiasmatic nucleus (SCN). To know the role of AVP neurons in the SCN, male rats were kept under a normal light-dark cycle (L-D), or under constant darkness (D-D) for 20 days. In L-D condition, AVP levels in the SCN showed the circadian change. In D-D condition, the patterns in AVP levels showed a free-running rhythm, and an about 12-h shift per 20 days. This result suggests that the activity of AVP neurons may be closely associated with the endogenous circadian rhythm of the SCN.