In all animals, the transition between night and day engages a host of physiological and behavioural rhythms. These rhythms depend not on the rods and cones of the retina, but on retinal ganglion cells (RGCs) that detect the ambient light level in the environment. These project to the suprachiasmatic nucleus (SCN) of the hypothalamus to entrain circadian rhythms that are generated within the SCN. The neuropeptide vasopressin has an important role in this entrainment. Many SCN neurons express vasopressin, and it has been assumed that the role of vasopressin in the SCN reflects the activity of these cells. Here we show that vasopressin is also expressed in many retinal cells that project to the SCN. Light-evoked vasopressin release contributes to the responses of SCN neurons to light, and enhances expression of the immediate early gene c-fos in the SCN, which is involved in photic entrainment of circadian rhythms.

In addition to its peripheral actions, oxytocin released within the brain is important for birth and essential for milk ejection. The oxytocinase enzyme (placental leucine aminopeptidase; P‐LAP ) is expressed both peripherally and centrally. P‐LAP controls oxytocin degradation in the uterus, placenta and plasma during pregnancy, although its role in the hypothalamus is unclear. We investigated P‐LAP expression and activity in the hypothalamus in virgin, pregnant and lactating rats, as well as its role in vivo during the milk‐ejection reflex. P‐LAP mRNA and protein were expressed in magnocellular neurones of the supraoptic ( SON ) and paraventricular ( PVN ) nuclei. Oxytocin neurones co‐expressed P‐LAP without strong subcellular co‐localisation of oxytocin and P‐LAP , indicating that they are packaged in separate vesicles. Examination of the intracellular distribution of oxytocin and P‐LAP showed a redistribution of P‐LAP to within 1 μm of the plasma membrane in the somata of oxytocin neurones during lactation. Both P‐LAP mRNA expression and hypothalamic leucyl/cystinyl aminopeptidase activity in the soluble fraction were higher during lactation than in late pregnant or virgin states. Inhibition of central enzyme activity by i.c.v. injection of amastatin in anaesthetised suckling mothers increased the frequency of reflex milk ejections. Because hypothalamic P‐LAP expression and activity increase in lactation, and the prevention of its action mimics central oxytocin administration, we conclude that P‐LAP regulates auto‐excitatory oxytocin actions during the suckling‐induced milk‐ejection reflex.

Intranasal administration has been widely used to investigate the effects of the neuropeptides vasopressin and oxytocin on human behaviour and neurological disorders, although exactly what happens when these neuropeptides are administered intranasally is far from clear. In particular, it is not clear whether a physiological significant amount of peptide enters the brain to account for the observed effects. In the present study, we investigated whether the intranasal administration of vasopressin and oxytocin to rats induces the expression of the immediate‐early gene productFos in brain areas that are sensitive to centrally‐administered peptide, whether it alters neuronal activity in the way that centrally‐administered peptide does, and whether it affects behaviour in the ways that are expected from studies of centrally‐administered peptide. We found that, whereas i.c.v. injection of very low doses of vasopressin or oxytocin increasedFos expression in several distinct brain regions, intranasal administration of large doses of the peptides had no significant effect. By contrast to the effects of vasopressin applied topically to the main olfactory bulb, we saw no changes in the electrical activity of olfactory bulb mitral cells after intranasal vasopressin administration. In addition, vasopressin given intranasally had no significant effects on social recognition or short‐term recognition memory. Finally, intranasal infusions of vasopressin had no significant effects on the parameters monitored on the elevated plus maze, a rodent model of anxiety. Our data obtained in rats suggest that, after intranasal administration, significant amounts of vasopressin and oxytocin do not reach areas in the brain at levels sufficient to change immediate early gene expression, neural activity or behaviour in the ways described for central administration of the peptides.

Although communication between neurons is considered a function of the synapse, neurons also release neurotransmitter from their dendrites. We found that dendritic transmitter release coordinates activity across distinct neuronal populations to generate integrative homeostatic responses. We show that activity-dependent vasopressin release from hypothalamic neuroendocrine neurons in the paraventricular nucleus stimulates neighboring (~100 μm soma-to-soma) presympathetic neurons, resulting in a sympathoexcitatory population response. This interpopulation crosstalk was engaged by an NMDA-mediated increase in dendritic Ca(2+), influenced by vasopressin's ability to diffuse in the extracellular space, and involved activation of CAN channels at the target neurons. Furthermore, we demonstrate that this interpopulation crosstalk plays a pivotal role in the generation of a systemic, polymodal neurohumoral response to a hyperosmotic challenge. Because dendritic release is emerging as a widespread process, our results suggest that a similar mechanism could mediate interpopulation crosstalk in other brain systems, particularly those involved in generating complex behaviors.

Central vasopressin facilitates social recognition and modulates numerous complex social behaviors in mammals, including parental behavior, aggression, affiliation, and pair-bonding. In rodents, social interactions are primarily mediated by the exchange of olfactory information, and there is evidence that vasopressin signaling is important in brain areas where olfactory information is processed. We recently discovered populations of vasopressin neurons in the main and accessory olfactory bulbs and anterior olfactory nucleus that are involved in the processing of social odor cues. In this review, we propose a model of how vasopressin release in these regions, potentially from the dendrites, may act to filter social odor information to facilitate odor-based social recognition. Finally, we discuss recent human research linked to vasopressin signaling and suggest that our model of priming-facilitated vasopressin signaling would be a rewarding target for further studies, as a failure of priming may underlie pathological changes in complex behaviors.

Magnocellular neurons of the supraoptic nucleus (SON) secrete oxytocin and vasopressin from axon terminals in the neurohypophysis, but they also release large amounts of peptide from their somata and dendrites, and this can be regulated both by activity-dependent Ca(2+) influx and by mobilization of intracellular Ca(2+). This somato-dendritic release can also be primed by agents that mobilise intracellular Ca(2+), meaning that the extent to which it is activity-dependent, is physiologically labile. We investigated the role of different Ca(2+) channels in somato-dendritic release; blocking N-type channels reduced depolarisation-induced oxytocin release from SONs in vitro from adult and post-natal day 8 (PND-8) rats, blocking L-type only had effect in PND-8 rats, while blocking other channel types had no significant effect. When oxytocin release was primed by prior exposure to thapsigargin, both N- and L-type channel blockers reduced release, while P/Q and R-type blockers were ineffective. Using confocal microscopy, we found immunoreactivity for Ca(v)1.2 and 1.3 channel subunits (which both form L-type channels), 2.1 (P/Q type), 2.2 (N-type) and 2.3 (R-type) in the somata and dendrites of both oxytocin and vasopressin neurons, and the intensity of the immunofluorescence signal for different subunits differed between PND-8, adult and lactating rats. Using patch-clamp electrophysiology, the N-type Ca(2+) current density increased after thapsigargin treatment, but did not alter the voltage sensitivity of the channel. These results suggest that the expression, location or availability of N-type Ca(2+) channels is altered when required for high rates of somato-dendritic peptide release.

Central vasopressin facilitates social recognition and modulates numerous complex social behaviors in mammals, including parental behavior, aggression, affiliation, and pair‐bonding. In rodents, social interactions are primarily mediated by the exchange of olfactory information, and there is evidence that vasopressin signaling is important in brain areas where olfactory information is processed. We recently discovered populations of vasopressin neurons in the main and accessory olfactory bulbs and anterior olfactory nucleus that are involved in the processing of social odor cues. In this review, we propose a model of how vasopressin release in these regions, potentially from the dendrites, may act to filter social odor information to facilitate odor‐based social recognition. Finally, we discuss recent human research linked to vasopressin signaling and suggest that our model of priming‐facilitated vasopressin signaling would be a rewarding target for further studies, as a failure of priming may underlie pathological changes in complex behaviors.

Oxytocin neurone activation at birth depends upon noradrenaline‐mediated signals from the uterus via a brainstem pathway, as well as on factors within the supraoptic nucleus (SON), including oxytocin itself, and the system adapts during pregnancy to optimise the delivery process. We determined whether noradrenaline release in the SON in response to stimuli activating brainstem inputs or antidromically activating magnocellular neurones is enhanced at term pregnancy. Noradrenaline, serotonin and dopamine concentrations were measured in microdialysis samples collected from the dorsal and ventral SON before, during and after either i.v. cholecystokinin (CCK) or neural stalk stimulation in virgin and late pregnant rats. Each stimulus transiently increased noradrenaline and serotonin but not dopamine concentration in the dorsal SON, and responses were increased on days 21 and 22 of pregnancy compared to day 20 pregnant and virgin rats. Neural stalk stimulation induced sensitisation to subsequent stalk stimulation and so the responses in the dorsal SON were doubled; on day 22 of pregnancy, the area under the curve of monoamine concentration was 3.4‐fold greater than in virgins, suggesting that adaptations perinatally enhance responsiveness. In conclusion, there are enhanced responses of noradrenaline and serotonin release in the SON that can generate very high, transient extracellular concentrations at term. This may be a consequence of neuroendocrine adaptations in late pregnancy and probably contributes to optimal oxytocin neurone activation during parturition.

Peptide hormones, like oxytocin or vasopressin, are well known to influence social behaviour in various mammalian species. While oxytocin is thought to be prosocial and enhance cooperation, vasopressin may function to trigger aggressive behavioural responses. In most mammals, the olfactory system is key to social recognition, and now a population of vasopressin-expressing interneurons in the olfactory bulb has been identified as being required for proper social recognition in rodents. The activity of these neurons, in response to vasopressin signalling, is linked directly to the modulation of information processing by the olfactory system. Although vasopressin itself may not play an identical role in humans, such an experience-dependent mechanism of hormone release underlying social recognition may be common. Peptide hormones such as oxytocin and vasopressin influence social behaviour in several mammalian species. Here it is shown that a population of interneurons in the rat olfactory bulb releases vasopressin, and that vasopressin signalling is required in the olfactory system for proper social recognition in rats. Although vasopressin may not work in exactly the same way in humans, social recognition mediated by experience-dependent vasopressin release may be common. Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours1. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader–Willi syndrome, affective disorders and obsessive–compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism2,3. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

The anterior olfactory nucleus (AON), a component of the main olfactory system, is a cortical region that processes olfactory information and acts as a relay between the main olfactory bulbs and higher brain regions such as the piriform cortex. Utilizing a transgenic rat in which an enhanced green fluorescent protein reporter gene is expressed in vasopressin neurones (eGFP-vasopressin), we have discovered a population of vasopressin neurones in the AON. These vasopressin neurones co-express vasopressin V1 receptors. They also co-express GABA and calbinin-D28k indicating that they are neurochemically different from the newly described vasopressin neurons in the main olfactory bulb. We utilized the immediate early gene product, early growth response protein 1 (Egr-1), to examine the functional role of these vasopressin neurons in processing social and non-social odours in the AON. Exposure of adult rats to a conspecific juvenile or a heterospecific predator odour leads to increases in Egr-1 expression in the AON in a subregion specific manner. However, only exposure to a juvenile increases Egr-1 expression in AON vasopressin neurons. These data suggest that vasopressin neurones in the AON may be selectively involved in the coding of social odour information.

Classically, neuropeptide release occurs from axon terminals to influence post-synaptic neurons. However, it has become increasingly clear that many neurons in the central nervous system also release neuropeptide from their somata and dendrites. This somato-dendritic neuropeptide release can have many functions, amongst which is feedback modulation of activity. In addition, most central neurons also co-express other neurotransmitters/neuromodulators alongside their principal neurotransmitter, yet the function of these co-expressed factors is largely unknown. With regard to the function of somato-dendritic neuropeptide release, hypothalamic vasopressin neurons are amongst the best understood neurons in the central nervous system. Vasopressin neurons co-express a number of other neuropeptides including apelin, dynorphin and galanin as well as the purine, adenosine triphosphate. In addition to factors co-released during exocytosis, vasopressin neurons also generate nitric oxide. Each of these factors has been demonstrated to influence the activity of vasopressin neurons. For at least some of these factors, modulation of the activity of vasopressin neurons is activity dependent; suggesting that autocrine feedback regulation of activity might be an important role for somato-dendritic release of neuromodulators across the central nervous system.

Apelin, a novel peptide originally isolated from bovine stomach tissue extracts, is widely but selectively distributed throughout the nervous system. Vasopressin and oxytocin are synthesized in the magnocellular neurons of the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus, which are apelin-rich regions in the central nervous system. We made extracellular electrophysiological recordings from the transpharyngeally exposed SON of urethane-anaesthetized rats to assess the role of apelin in the control of the firing activity of identified magnocellular vasopressin and oxytocin neurons in vivo. Apelin-13 administration onto SON neurons via microdialysis revealed cell-specific responses; apelin-13 increased the firing rates of vasopressin cells but had no effect on the firing rate of oxytocin neurons. A direct excitatory effect of apelin-13 on vasopressin cell activity is also supported by our in vitro studies showing depolarization of membrane potential and increase in action potential firing. To assess the effects of apelin-13 on somatodendritic peptide release, we used in vitro release studies from SON explants in combination with highly sensitive and specific RIA. Apelin-13 decreases basal (by 78%; P < 0.05; n = 6) and potassium-stimulated (by 57%; P < 0.05; n = 6) vasopressin release but had no effect on somatodendritic oxytocin release. Taken together, our data suggest a local autocrine feedback action of apelin on magnocellular vasopressin neurons. Furthermore, these data show a marked dissociation between axonal and dendritic vasopressin release with a decrease in somatodendritic release but an increase in electrical activity at the cell bodies, indicating that release from these two compartments can be regulated wholly independently.

Oxytocin has potent central effects on feeding behaviour, as well as on social and sexual behaviours, and one likely substrate for its anorectic effect is the ventromedial nucleus of the hypothalamus. This nucleus expresses a high density of oxytocin receptors, but contains very few oxytocin-containing fibres, hence it is a likely target of 'neurohormonal' actions of oxytocin, including possibly oxytocin released from the dendrites of magnocellular oxytocin neurones. As oxytocin release from dendrites is regulated independent of electrical activity and of secretion from the neurohypophysis, exactly how this release is regulated by metabolic and reproduction-related signals remains to be established fully. Intriguingly though, it looks as though this central release of oxytocin from magnocellular neurons might be instrumental in a fundamental shift in motivational behaviour — switching behaviour from being driven by the need to find and consume food, to the need to reproduce.