Supraoptic nucleus

The supraoptic nucleus is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm, and, in humans, it contains about 3,000 neurons. The cell bodies produce two closely-related peptide hormones, vasopressin and oxytocin. Every supraoptic neuron is thought to make either oxytocin or vasopressin, although a few make both. In the cell bodies, the hormones are packaged in large, membrane-bound vesicles which are transported down the axons to the nerve endings. Similar magnocellular neurons are also found in the paraventricular nucleus.

Every (or nearly every) neuron in the nucleus has one long axon that projects to the posterior pituitary gland, where it gives rise to about 10,000 neurosecretory nerve terminals. The magnocellular neurons are electrically excitable: In response to afferent stimuli from other neurons, they generate action potentials which propagate down the axons. When an action potential invades a neurosecretory terminal, the terminal is depolarised, and calcium enters the terminal through voltage-gated channels. The calcium entry triggers the secretion of some of the vesicles by a process known as exocytosis. The vesicle contents are released into the extracellular space, from where they diffuse into the bloodstream.

Regulation of supraptic neurons
Vasopressin is secreted from the pituitary gland in response to an increase in the sodium concentration of the blood (such as after a period of dehydration), or in response to a fall in the volume of the blood (such as after hemorrhage). Vasopressin acts at the kidneys to promote resorption of water (antidiuresis), producing a more concentrated urine. Vasopressin also constricts many peripheral blood vessels.

Oxytocin is secreted in large amounts during birth, when it causes the uterus to contract, thus assisting in expelling the fetus from the birth canal. Oxytocin secretion also plays an essential role in lactation; oxytocin acts at the mammary gland to cause milk to be let down in response to suckling. Many other stimuli can cause the secretion of oxytocin and vasopressin, but these are thought to be the most important physiological factors.

For vasopressin and oxtocin to be secreted at appropriate times, the cell bodies must be activated by relevant stimuli (see 1-4). The electrical activity of supraoptic neurons is regulated by inputs from many different brain regions. Some inputs come from structures adjacent to the anterior wall of the third ventricle (the subfornical organ, the organum vasculosum of the lamina terminalis, and the nucleus medianus); these provide information relevant for the regulation of body fluid and electrolyte homeostasis, in which the secretion of vasopressin plays a particularly important role.

Some other inputs come from the brainstem, including from some of the noradrenergic neurons of the nucleus of the solitary tract and the ventrolateral medulla. However many of the direct inputs to the supraoptic nucleus come from neurons just outside the nucleus (the "perinuclear zone"). Oxytocin neurons respond to stimulation of the nipples (resulting in milk let-down) and in response to uterine contractions and distension of the birth canal (the "Ferguson reflex"), but the pathways by which these stimuli reach the neurons are not fully known.

Of the afferent inputs to the supraoptic nucleus, most contain either the inhibitory neurotransmitter GABA or the excitatory neurotransmitter glutamate, but these transmitters often co-exist with various peptides. Other afferent neurotransmitters include noradrenaline (from the brainstem), dopamine, serotonin and acetylcholine.

The supraoptic nucleus as a "model system"
The supraoptic nucleus is an important "model system" in neuroscience. There are many reasons for this: some technical advantages of working on the supraoptic nucleus are that the cell bodies are relatively large, the cells make exceptionally large amounts of their secretory products, and the nucleus is relatively homogeneous and easy to separate from other brain regions. The gene expression and electrical activity of supraoptic neurons has been studied extensively, in many physiological and experimental conditions (6). These studies have led to many insights of general importance, as in the examples below.

Morphological plasticity in the supraoptic nucleus
Anatomical studies using electron microscopy have shown that the morphology of the supraoptic nucleus is remarkably adaptable (7-9). For example, during lactation there are large changes in the size and shape of the oxytocin neurons, in the numbers and types of synapses that these neurons receive, and in the structural relationships between neurons and glial cells in the nucleus. These changes arise during parturition, and are thought to be important adaptations that prepare the oxytocin neurons for a sustained high demand for oxytocin. Oxytocin is essential for milk let-down in response to suckling.

These studies showed that the brain was much more "plastic" in its anatomy than previously recognised, and led to great interest in the interactions between glial cells and neurons generally.

Pulsatile hormone secretion
In 1973, Jonathan Wakerley was a graduate student working in Bristol under the supervision of Dennis Lincoln. In a series of elegant experiments (10), Wakerley showed the behavior of oxytocin neurons in response to the suckling stimulus. By recording the electrical activity of single neurons in the supraoptic nucleus of anesthetised rats, he showed that,in response to suckling, the oxytocin neurons discharge action potentials in brief intense synchronised bursts. These bursts occurred ever few minutes while the pups were suckling at the nipples, and each burst caused the release of a large pulse of oxytocin into the blood that resulted in a large rise in intramammary pressure, reflecting acute milk let-down. Similar bursts of electrical activity occur during parturition, associated with each birth (5).

The importance of these experiments was in showing that the role of the hypothalamus was to produce a patterned response to the continuous stimulus of suckling. For oxytocin to be effective in causing milk let down, it is important that it is released in large, discrete pulses - if oxytocin is delivered continuously rather than in pulses, the mammary gland rapidly desensitises (4).

Before these experiments, it was often assumed that the concentrations of circulating hormones change relatively slowly. These experiments prompted researchers to study the temporal pattern of hormone secretion much more closely. They found that many hormones, including most of the hormones secreted from the anterior pituitary gland, are also released in pulses, and that these pulsatile patterns are very important for the biological efficacy of the hormonal signals.

Stimulus-secretion coupling
In response to, for instance, a rise in the plasma sodium concentration, vasopressin neurons also discharge action potentials in bursts, but these bursts are much longer and are less intense than the bursts displayed by oxytocin neurons, and the bursts in vasopressin cells are not synchronised (1).

It seemed strange that the vasopressin cells should fire in bursts. As the activity of the vasopressin cells is not synchronised, the overall level of vasopressin secretion into the blood is continuous, not pulsatile. Richard Dyball and his co-workers speculated that this pattern of activity, called "phasic firing", might be particularly effective for causing vasopressin secretion. They showed this to be the case (11) by studying vasopressin secretion from the isolated posterior pituitary gland in vitro. They found that vasopressin secretion could be evoked by electrical stimulus pulses applied to the gland, and that much more hormone was released by a phasic pattern of stimulation than by a continuous pattern of stimulation.

These experiments led to interest in "stimulus-secretion coupling" - the relationship between electrical activity and secretion. Supraoptic neurons are unusual because of the large amounts of peptide that they secrete, and because they secrete the peptides into the blood. However many neurons in the brain, and especially in the hypothalamus, synthesize peptides. It is now thought that bursts of electrical activity might be generally important for releasing large amounts of peptide from peptide-secreting neurons.

Dendritic secretion
Supraoptic neurons have typically 1-3 large dendrites, most of which project ventrally to form a mat of process at the base of the nucleus, called the ventral glial lamina. The dendrites receive most of the synaptic terminals from afferent neurons that regulate the supraoptic neurons, but neuronal dendrites are often actively involved in information processing, rather than than being simply passive receivers of information. The dendrites of supraoptic neurons contain large numbers of neurosecretory vesicles that contain oxytocin and vasopressin, and they can be released from the dendrites by exocytosis. The oxytocin and vasopressin that is released at the posterior pituitary gland enters the blood, and cannot re-enter the brain because the blood-brain barrier does not allow oxytocin and vasopressin through, but the oxytocin and vasopressin that is released from dendrites acts within the brain. Oxytocin neurons themselves express oxytocin receptors, and vasopressin neurons express vasopressin receptors, so dendritically-released peptides "autoregulate" the supraoptic neurons. Francoise Moos and Phillipe Richard first showed that the autoregulatory action of oxytocin is important for the milk-ejection reflex.

These peptides have relatively long half-lives in the brain (about 20 minutes in the CSF), and they are released in large amounts in the supraoptic nucleus, and so they are available to diffuse through the extracellular spaces of the brain to act at distant targets. Oxytocin and vasopressin receptors are present n many other brain regions, including the amygdala, brainstem, septum, and most other nuclei in the hypothalamus

Because so much vasopressin and oxytocin are released at this site, studies of the supraoptic nucleus have made an important contribution to understanding how release from dendrites is regulated, and in understanding its physiological significance.

Co-existing peptides
Vasopressin neurons and oxytocin make many other neuroactive substances in addition to vasopressin and oxytocin, though most are present only in small quantities. However, some of these other substances are known to be important. Dynorphin produced by vasopressin neurons is involved in regulating the phasic discharge patterning of vasopressin neurons, and nitric oxide produced by both neuronal types is a negative-feedback regulator of cell activity. Oxytocin neurons also make dynorphin, in these neurons, dynorphin acts at the nerve terminals in the posterior pituitary as a negative feedback inhibitor of oxytocin secretion. Oxytocin neurons also make large amounts of cholecystokinin and cocaine-and amphetamine regulatory transcript (CART).