Water retention in the kidney is known to be an active phenomenon, controlled by a neuropeptide: vasopressin. Water excretion was assumed to be a passive phenomenon, as a result of vasopressin release blockade. This simplistic view is incorrect because water excretion is also controlled by a diuretic neuropeptide, apelin, produced not only by several peripheral tissues, but also by hypothalamic neurons, in particular the vasopressin ones projecting to the posterior pituitary.

Normal aging is associated with vasopressin neuron adaptation, but little is known about its effects on the release of apelin, an aquaretic peptide colocalized with vasopressin. We found that plasma vasopressin concentrations were higher and plasma apelin concentrations lower in aged rats than in younger adults. The response of AVP/apelin neurons to osmotic challenge was impaired in aged rats. The overactivity of vasopressin neurons was sustained partly by the increased expression of Transient receptor potential vanilloid2 (Trpv2), because central Trpv blocker injection reversed the age-induced increase in plasma vasopressin concentration without modifying plasma apelin concentration. The morphofunctional plasticity of the supraoptic nucleus neuron-astrocyte network normally observed during chronic dehydration in adults appeared to be impaired in aged rats as well. IL-6 overproduction by astrocytes and low-grade microglial neuroinflammation may contribute to the modification of neuronal functioning during aging. Indeed, central treatment with antibodies against IL-6 decreased plasma vasopressin levels and increased plasma apelin concentration toward the values observed in younger adults. Conversely, minocycline treatment (inhibiting microglial metabolism) did not affect plasma vasopressin concentration, but increased plasma apelin concentration toward control values for younger adults. This study is the first to demonstrate dual vasopressin/apelin adaptation mediated by inflammatory molecules and neuronal Trpv2, during aging.

Water retention in the kidney is known to be an active phenomenon, controlled by a neuropeptide: vasopressin. Water excretion was assumed to be a passive phenomenon, as a result of vasopressin release blockade. This simplistic view is incorrect because water excretion is also controlled by a diuretic neuropeptide, apelin, produced not only by several peripheral tissues, but also by hypothalamic neurones, in particular the vasopressin ones projecting to the posterior pituitary.

Apelin is a bioactive peptide identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ in 1998. The present data show that apelin modulates the activity of magnocellular and parvocellular oxytocin (OXY) neurons in the lactating rat. A combination of in situ hybridization and immunohistochemistry demonstrated the presence of apelin receptor mRNA in hypothalamic OXY neurons. Double immunofluorescence labeling then revealed the colocalization of apelin with OXY in about 20% of the hypothalamic OXY-positive neurons. Intracerebroventricular apelin administration inhibited the activity of magnocellular and parvocellular OXY neurons, as shown by measuring the c-fos expression in OXY neurons or by direct electrophysiological measurements of the electrical activity of these neurons. This effect was correlated with a decrease in the amount of milk ejected. Thus, apelin inhibits the activity of OXY neurons through a direct action on apelin receptors expressed by these neurons in an autocrine and paracrine manner. In conclusion, these findings highlight the inhibitory role of apelin as an autocrine/paracrine peptide acting on OXY neurons during breastfeeding.

During the course of an infection, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) acts in the brain to trigger development of behavioral responses, collectively termed sickness behavior. Biological activities of TNFα can be mediated by TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2). TNFα activates neutral sphingomyelinase through the TNF-R1 adapter protein FAN (factor associated with neutral sphingomyelinase activation), but a behavioral role of FAN in the brain has never been reported.

The increase of plasma arginin-vasopressin (AVP) release, which translates hypothalamic AVP neuron activation in response to immune challenge, appears to occur independently of plasma osmolality or blood pressure changes. Many studies have shown that major inflammatory mediators produced in response to peripheral inflammation, such as prostaglandin (PG)-E(2) and interleukin (IL)-1beta, excite AVP neurons. However, in vivo electrical activation of AVP neurons was still not assessed in relation to plasma AVP release, osmolality, or blood pressure or to the expression and role of inflammatory molecules like PG-E(2), IL-1beta, IL-6, and tumor necrosis factor-alpha (TNFalpha). This study aims at elucidating those factors that underlie the activation of AVP neurons in response to immune stimulation mimicked by an intraperitoneal injection of lipopolysaccharide (LPS) in male Wistar rats. LPS treatment concomittanlty decreased diuresis and increased plasma AVP as well as AVP neuron activity in vivo, and these effects occurred as early as 30 min. Activation was sustained for more than 6 h. Plasma osmolality did not change, whereas blood pressure only transiently increased during the first hour post-LPS. PG-E(2), IL-1beta, and TNFalpha mRNA expression were raised 3 h after LPS, whereas IL-6 mRNA level increased 30 min post-LPS. In vivo electrophysiological recordings showed that brain IL-6 injection increased AVP neuron activity similarly to peripheral LPS treatment. In contrast, brain injection of anti-IL-6 antibodies prevented the LPS induced-activation of AVP neurons. Taken together, these results suggest that the early activation of AVP neurons in response to LPS injection is induced by brain IL-6.

When young suckle, they are rewarded intermittently with a let-down of milk that results from reflex secretion of the hormone oxytocin; without oxytocin, newly born young will die unless they are fostered. Oxytocin is made by magnocellular hypothalamic neurons, and is secreted from their nerve endings in the pituitary in response to action potentials (spikes) that are generated in the cell bodies and which are propagated down their axons to the nerve endings. Normally, oxytocin cells discharge asynchronously at 1-3 spikes/s, but during suckling, every 5 min or so, each discharges a brief, intense burst of spikes that release a pulse of oxytocin into the circulation. This reflex was the first, and is perhaps the best, example of a physiological role for peptide-mediated communication within the brain: it is coordinated by the release of oxytocin from the dendrites of oxytocin cells; it can be facilitated by injection of tiny amounts of oxytocin into the hypothalamus, and it can be blocked by injection of tiny amounts of oxytocin antagonist. Here we show how synchronized bursting can arise in a neuronal network model that incorporates basic observations of the physiology of oxytocin cells. In our model, bursting is an emergent behaviour of a complex system, involving both positive and negative feedbacks, between many sparsely connected cells. The oxytocin cells are regulated by independent afferent inputs, but they interact by local release of oxytocin and endocannabinoids. Oxytocin released from the dendrites of these cells has a positive-feedback effect, while endocannabinoids have an inhibitory effect by suppressing the afferent input to the cells.

This review concentrates on the characteristics and functionality of endocrine neurons in the hypothalamo-neurohypophysial system, coexpressing two peptides, vasopressin and apelin. Vasopressin is synthesized in the soma of magnocellular neurons, then packaged in granules with its respective receptors. In these neurons, apelin is generated from a larger precursor proapelin and is detected in vesicles, some of them colocalize with vasopressin, for others there is a marked segregation of apelin and vasopressin immunoreactivity along the hypothalamo-hypophyseal axons. Furthermore, apelin receptors, like V1a-type and V1b-type vasopressin receptors, are synthesized by magnocellular vasopressin neurons. In lactating rodents, apelin given intracerebroventricularly inhibited the phasic electrical activity of vasopressin neurons, reduced plasma vasopressin levels and increased aqueous diuresis, showing that apelin acts as a potent diuretic neuropeptide, counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Moreover, in response to potent physiological stimuli known to evoke increased phasic activity of vasopressin neurons (hyper-osmolarity like during dehydration), both the soma dendrites and neurohypophysial terminals loose their dense staining quality, and vasopressin is released by (i) dendrites in the extracellular space to optimize the characteristic phasic activity necessary to a sustained release of vasopressin and (ii) by terminals in blood circulation where vasopressin then ensures its main endocrine actions at kidney level (antidiuretic effect). Conversely, apelin accumulates in these neurons rather than being released into the bloodstream and probably into the nuclei. Thus, decreases in the local supply of apelin to magnocellular vasopressin cell bodies may facilitate the expression by vasopressin neurons of an optimized phasic activity, by decreasing the inhibitory actions of apelin on these neurons. Antagonistic regulation of apelin and vasopressin has a biological purpose, making it possible to maintain the water balance of the organism by preventing additional water loss via kidneys. This reveals a new physiological concept of dual and opposite functional potentiality for endocrine neurons coexpressing different neuropeptides in separate vesicles: depending on the degree of their electrical activation/inhibition, neurons release selectively the very coexpressed peptides that will ensure its accurate endocrine functions in perfect accordance with the hormonal demand.

variety of pathogenic insults cause synthesis of tumor necrosis factor (TNF)alpha in the brain, resulting in sickness behavior. Here we used TNF-receptor (TNF-R)2-deficient and wild-type mice to demonstrate that the reduction in social exploration of a novel juvenile, the increase in immobility and the loss of body weight caused by central TNF alpha (i.c.v., 50 ng/mouse) are blocked by central pre-treatment with the multifunctional peptide, insulin-like growth factor (IGF-I; i.c.v., 300 ng/mouse). These results establish that sickness behavior induced by central TNFa via the TNF-R1 (p55) is directly opposed by IGF-I in the brain. (c) 2007 Elsevier B.V. All rights reserved.

Oxytocin (OT) and vasopressin (VP) autocontrol their secreting neurons in the supraoptic nucleus (SON) by modulating action potential firing through activation of specific metabotropic receptors. However, the mechanisms linking receptor activation to firing remain unknown. In almost all cell types, activation of plasma membrane metabotropic receptors triggers signalling cascades that induce mobilization of calcium from intracellular stores. In turn, emptying the calcium stores may evoke calcium influx through store-operated channels (SOCs), the functions of which remain largely unknown in neurons. In this study, we show that these channels play a key role in the SON, at least in the response to OT. In isolated rat SON neurons, store depletion by thapsigargin induced an influx of calcium, demonstrating the presence of SOCs in these neurons. This calcium influx was specifically inhibited by 0.2 m(M) 1-(2-trifluoromethylphenyl-)imidazole (TRIM). At 2 m(M), this compound affected neither the resting electrophysiological properties nor the voltage-dependant inward currents. In fresh slices, TRIM (2 m(M)) did not affect the resting potential of SON neurons, action potential characteristics, spontaneous action potential firing or synaptic activity; this compound thus appears to be a specific blocker of SOCs in SON neurons. TRIM (0.2 m(M)) specifically reduced the increase in action potential firing triggered by OT but did not affect the VP-induced response. These observations demonstrate that store operated channels exist in hypothalamic neurons and specifically mediate the response to OT in the SON.

Many neurotransmitters exert an autocrine control at axon terminals via autoreceptors that modulate activity-dependent exocytosis; less classical, and more complex, is the autocontrol exerted at soma and dendrites. One interesting example is provided by vasopressin neurones of the hypothalamo–neurohypophysial system, especially as the physiological relevance of the autocontrol has been widely studied. During sustained hormonal demand, vasopressin neurones adopt a phasic pattern of activity, with alternating active and silent periods (bursts), that each last 10–40 s. This phasic pattern is particularly efficient for the release of vasopressin, but the bursts are not co-ordinated between vasopressin neurones, so vasopressin is released continuously into the circulation, ensuring its effectiveness at peripheral targets. The phasic patterning of vasopressin neurones depends upon intrinsic membrane properties. Synaptic inputs to vasopressin neurones appear to arrive randomly, and bursts are initiated from summation of excitatory postsynaptic potentials (EPSPs). Each spike is followed by a prominent, long lasting (1–3 s), non-synaptic depolarizing after-potential (DAP) (Andrew & Dudek, 1983); consecutive spikes lead to summation of DAPs, and a resulting, long-lasting plateau potential sustains burst firing. As a burst progresses, DAPs, and plateau potentials undergo pronounced activity-dependent inactivation, and it is believed that this inactivation ultimately leads to termination of the burst. Thus, bursts are both sustained and terminated by activity-dependent modulation of intrinsic membrane properties. The intrinsic properties that underlie phasic patterning are regulated by autocrine–paracrine control. From the soma and dendrites of vasopressin neurones, neurosecretory granules are secreted by exocytosis in response to specific physiological stimuli. In these granules, vasopressin is co-stored with several molecules including ATP and dynorphin, and interestingly, the granules also contain vasopressin receptors and κ-opioid receptors. This co-localization facilitates binding of the peptides to their receptors at exocytosis. Dendritic release is partly activity dependent and partly self-sustaining, since vasopressin itself can elicit dendritic release without increasing electrical activity. In vivo, vasopressin modulates the phasic pattern of vasopressin neurones depending on their initial electrical activity: fast-firing neurones are slowed, and slow-firing neurones are excited. Thereby, vasopressin fosters the population of vasopressin neurones to express the phasic pattern of activity that is most efficient for vasopressin release from the axon terminals (Gouzenes et al. 1998). At the soma and dendrites of vasopressin neurones, vasopressin, via actions at V1a and V1b receptors that involve different intracellular second messenger pathways, induces both mobilization of intracellular Ca2+ and Ca2+ entry. The role of the V1b receptor is unclear, but there is now consensus that the inhibitory effect of vasopressin on phasic patterning involves V1a receptor activation. The effect of vasopressin on autoreceptors is complemented by a presynaptic action on afferent terminals, involving inhibition of glutamate release (Kombian et al. 2000). The autocrine–paracrine control also involves co-stored and co-released molecules, including in particular dynorphin. Both vasopressin and dynorphin (Brown et al. 1998) restrain the activity of phasic neurones. As reported in the previous issue of The Journal of Physiology, Brown & Bourque (2004) made intracellular recordings of vasopressin neurones from hypothalamic explants to explore the possibility that endogenous dynorphin restrains vasopressin neurones by an autocrine action on intrinsic membrane properties. DAPs and plateau potentials were evoked by triggering brief trains of spikes with depolarizing current pulses. DAPs that are evoked soon after a preceding evoked DAP are attenuated, and this effect is similar to that observed when DAPs are evoked soon after a spontaneous burst. The degree of attenuation depends on the number of spikes elicited before the evoked DAP, demonstrating that DAPs undergo pronounced activity-dependent inactivation that will reduce the probability of generation of spontaneous spikes as the burst progresses. Brown & Bourque (2004) then used pharmacological tools to demonstrate that dendritically released dynorphin generates this activity-dependent inhibition. First, inducing neurosecretory vesicle depletion by application of the black widow spider venom, α-latrotoxin, reduced activity-dependent DAP inhibition. Second, the action of α-latrotoxin was prevented by κ-opioid receptor antagonists but not by vasopressin receptor antagonists. Third, activity-dependent κ-opioid inhibition of DAPs does not result from actions on evoked after-hyperpolarizations since these are not affected by κ-opioid receptor antagonism. This suggests that the Ca2+-dependent K+ conductances that underlie after-hyperpolarizations are not involved in activity-dependent κ-opioid inhibition of DAPs. The study brings clear evidence of modulation of intrinsic membrane properties of vasopressin neurones by endogenous feedback, in this case by dendritic dynorphin release. It also clarifies the different roles of different, co-released, peptides: vasopressin decreases EPSCs via V1a receptors, while dynorphin inhibits DAPs via κ-opioid receptors. The development of the restraint exerted by each peptide also differs: restraint by vasopressin is sustained throughout each burst, while the effects of dynorphin emerge progressively as the burst develops (Brown et al. 2004). A final question pertains to the mechanisms underlying this temporal dissociation in the actions of vasopressin and dynorphin. This may be related to the respective concentration of the two peptides in neurosecretory vesicles (vasopressin is more abundant than dynorphin), to differential accumulation rates in the extracellular space, or to differential degradation by extracellular peptidases. However, it more probably results from the different ways that the two neuropeptides affect rhythmogenesis. Since EPSCs are randomly patterned, reduction of EPSC amplitude by vasopressin should result in a general reduction in excitability. Conversely, modulation of activity-dependent DAPs would be expected to also be activity dependent. These studies lay the foundations for further studies on action of co-stored and co-released molecules implicated in the control of neuronal excitability and provide useful trails for investigating their roles in the patterning of electrical activity of neurones in the CNS.

Maintenance of osmotic pressure is a primary regulatory process essential for normal cell function. The osmolarity of extracellular fluids is regulated by modifying the intake and excretion of salts and water. A major component of this regulatory process is the neuroendocrine hypothalamo-neurohypophysial system, which consists of neurons located in the paraventricular and supraoptic nuclei. These neurons synthesize the neurohormones vasopressin and oxytocin and release them in the blood circulation. We here review the mechanisms responsible for the osmoregulation of the activity of these neurons. Notably, the osmosensitivity of the supraoptic nucleus is described including the recent data that suggests an important participation of taurine in the transmission of the osmotic information. Taurine is an amino acid mainly known for its involvement in cell volume regulation, as it is one of the major inorganic osmolytes used by cells to compensate for changes in extracellular osmolarity. In the supraoptic nucleus, taurine is highly concentrated in astrocytes, and released in an osmodependent manner through volume-sensitive anion channels. Via its agonist action on neuronal glycine receptors, taurine is likely to contribute to the inhibition of neuronal activity induced by hypotonic stimuli. This inhibitory influence would complement the intrinsic osmosensitivity of supraoptic neurons, mediated by excitatory mechanoreceptors activated under hypertonic conditions. These observations extend the role of taurine from the regulation of cell volume to that of the whole body fluid balance. They also point to a new role of supraoptic glial cells as active components in a neuroendocrine regulatory loop.