Supraoptic nucleus

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Human supraoptic nucleus (SON, dorsolateral and ventromedial components) in this coronal section is indicated by the shaded areas. Dots represent vasopressin (AVP) neurons (also seen in the paraventricular nucleus, PVN). The medial surface is the 3rd ventricle (3V), with more lateral to the left.

The supraoptic nucleus (SON), in the hypothalamus of the mammalian brain, is a nucleus of magnocellular neurosecretory cells. It is situated at the base of the brain, adjacent to the optic chiasm, and, in rats, it contains about 3,000 large, neurosecretory neurons. The cell bodies of these neurons 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 2,000 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 supraoptic 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 is essential during 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 oxytocin to be secreted at appropriate times, the cell bodies must be activated by relevant stimuli. The electrical activity of supraoptic neurons is regulated by inputs from many different brain regions. Some inputs come from a group of brain 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 areas, so-called "circumventricular organs", provide information that is particularly relevant for body fluid and electrolyte homeostasis, in which vasopressin secretion plays an 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 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 - including somatostatin, angiotensin, neuropeptide Y and many others. Other afferent neurotransmitters include noradrenaline (from the caudal brainstem), dopamine, serotonin, histamine 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[1]. These studies have led to many insights of general importance, as in the examples below.

Morphological plasticity

Anatomical studies using electron microscopy have shown that the morphology of the supraoptic nucleus is remarkably adaptable.[2] 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

A "milk-ejection burst" of action potentials, recorded (with a microelectrode) from a single oxytocin neuron in the rat supraoptic nucleus. In a lactating rat, in response to suckling, oxytocin neurons display such bursts every few minutes. .[3]

In 1973, Jonathan Wakerley was a graduate student working in Bristol under the supervision of Dennis Lincoln. In a series of elegant experiments[4], 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 caused the release of a large pulse of oxytocin into the blood that produced a large rise in intramammary pressure, reflecting sudden 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 [6].

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

Phasic bursting activity recorded from a single vasopressin neuron in the rat supraoptic nucleus, plotted as the number of action potentials (spikes) recorded per second.

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 they are not synchronised [7].

It seemed strange that the vasopressin cells should fire in bursts. As the activity of the vasopressin cells is not synchronised, the overall pattern 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 [8] by studying vasopressin secretion from the isolated posterior pituitary gland in vitro. Vasopressin secretion could be evoked by electrical stimuli applied to the gland, and that much more was secreted with a phasic pattern of stimulation than with a continuous pattern.

These experiments led to interest in "stimulus-secretion coupling" - the relationship between electrical activity and secretion. Supraoptic neurons make very large amounts of the peptides that they secrete, because they secrete these peptides into the blood and must maintain large circulating concentrations. 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 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 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 have receptors for oxytocin, and vasopressin neurons have 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), so the large amounts that are released in the supraoptic nucleus have time to diffuse through the extracellular spaces of the brain to act at distant targets. Oxytocin and vasopressin receptors are present in many other brain regions, including the amygdala, brainstem, septum, and most other nuclei in the hypothalamus

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

Co-existing neuroactive substances

Vasopressin neurons and oxytocin neurons make many other neuroactive substances as well. Most are present only in small quantities, but some of these other substances are known to be important. The endogenous opioid peptide dynorphin produced by vasopressin neurons regulates 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 that 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). Oxytocin neurons also express corticotropin-releasing hormone during hypernatremia.


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