The multiple faces of the oxytocin and vasopressin systems in the brain.

Classically, hypothalamic neuroendocrine cells that synthesise oxytocin and vasopressin were categorised in two major cell types: the magnocellular and parvocellular neurones. It was assumed that magnocellular neurones project exclusively to the pituitary gland where they release oxytocin and vasopressin into the systemic circulation. The parvocellular neurones, on the other hand, project within the brain to regulate discrete brain circuitries and behaviours. Within the last few years, it has become evident that the classical view of these projections is outdated. It is now clear that oxytocin and vasopressin in the brain are released extrasynaptically from dendrites and from varicosities in distant axons. The peptides act principally to modulate information transfer through conventional synapses (such as glutamate synapses) by actions at respective receptors that may be preferentially localised to synaptic regions (on either side of the synapse) to alter the 'gain' of conventional synapses.

Social creatures: Model animal systems for studying the neuroendocrine mechanisms of social behaviour.

The interaction of animals with conspecifics, termed social behaviour, has a major impact on the survival of many vertebrate species. Neuropeptide hormones modulate the underlying physiology that governs social interactions, and many findings concerning the neuroendocrine mechanisms of social behaviours have been extrapolated from animal models to humans. Neurones expressing neuropeptides show similar distribution patterns within the hypothalamic nucleus, even when evolutionarily distant species are compared. During evolution, hypothalamic neuropeptides and releasing hormones have retained not only their structures, but also their biological functions, including their effects on behaviour. Here, we review the current understanding of the mechanisms of social behaviours in several classes of animals, such as worms, insects and fish, as well as laboratory, wild and domesticated mammals.

Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin.

The mammalian hypothalamic magnocellular neurons of the supraoptic and paraventricular nuclei are among the best understood of all peptidergic neurons. Through their anatomical features, vasopressin- and oxytocin-containing neurons have revealed many important aspects of dendritic functions. Here, we review our understanding of the mechanisms of somato-dendritic peptide release, and the effects of autocrine, paracrine and hormone-like signalling on neuronal networks and behaviour.

Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks.

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.

Are neuropeptides brain hormones?

Neurones use many different chemical signals to communicate information, including more than 100 different peptides. Many of these neuropeptides evoke specific and coherent behaviours and have been linked to a number of neurological disorders. Increasingly, we are recognising that peptide signals play a role in information processing that is quite unlike that of conventional neurotransmitters.

Neurotransmitters and peptides: whispered secrets and public announcements.

The magnocellular oxytocin and vasopressin neurones of the hypothalamus are now understood in exceptional detail. Extensive quantitative details from many independent sources are available describing the electrical activity of the neurones in diverse circumstances, the subcellular localization of vesicles, and rates of hormone secretion from nerve endings into the blood and from dendrites into the brain. These data enable the relationship of electrical (spike) activity to vesicle exocytosis to be inferred with some precision. Such calculations lead to the conclusion that exocytosis of peptide-containing vesicles is a relatively rare event even in this vesicle-dense system. At any given release site in the neurohypophysis, it seems that several hundred spikes are needed on average to release a single vesicle. Release from compartments within the brain seems also to be very rare, making it implausible that peptides can act in a temporally precise, anatomically specific manner. However, very large amounts of peptide are released by these infrequent events, consistent with their likely role as neurohormonal messengers.

The effects of apelin on the electrical activity of hypothalamic magnocellular vasopressin and oxytocin neurons and somatodendritic Peptide release.

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.

TFF3 induced Fos protein expression in the magnocellular oxytocin neurons of the hypothalamus.

TFF3 is synthesized in magnocellular oxytocin neurons of the supraoptic (SON) and paraventricular nuclei (PVN) of the rat and human hypothalamus. Here we investigated whether intracerebroventricular (i.c.v.) injection of TFF3 stimulates oxytocin release into the blood and activates Fos protein immunoreactivity in oxytocin neurons of the SON and PVN in rats. The results show that plasma oxytocin concentrations were not altered after i.c.v. injection of TFF3 or vehicle. Fos protein expression was significantly increased in both the SON and PVN after TFF3 injections and double labeling studies showed that the Fos signal was predominantly in oxytocin neurons.

Talking back: dendritic neurotransmitter release.

Classical transmitters and neuropeptides can be released from the dendrites of many neuronal populations, to act as retrograde signals that modulate synaptic transmission, electrical activity and, in some cases, morphology of the cell of origin. For the hypothalamic neuroendocrine cells that release vasopressin and oxytocin, the stimuli, mechanisms and physiological functions of dendritic release have been revealed in detail that is not yet available for other neurons. The regulation of dendritic transmitter release is complex and at least partially independent from axon terminal release. Here, we provide an overview of recent findings on the mechanisms and physiological consequences of dendritic neuropeptide release and place this in the context of discoveries of dendritic neurotransmitter release in other brain regions.