The hypothalamic supraoptic and paraventricular nuclei contain magnocellular neurosecretory cells (MNCs) that project to the posterior pituitary gland where they secrete either oxytocin or vasopressin (the antidiuretic hormone) into the circulation. Oxytocin is important for delivery at birth and is essential for milk ejection during suckling. Vasopressin primarily promotes water reabsorption in the kidney to maintain body fluid balance, but also increases vasoconstriction. The profile of oxytocin and vasopressin secretion is principally determined by the pattern of action potentials initiated at the cell bodies. Although it has long been known that the activity of MNCs depends upon afferent inputs that relay information on reproductive, osmotic and cardiovascular status, it has recently become clear that activity depends critically on local regulation by glial cells, as well as intrinsic regulation by the MNCs themselves. Here, we provide an overview of recent advances in our understanding of how intrinsic and local extrinsic mechanisms integrate with afferent inputs to generate appropriate physiological regulation of oxytocin and vasopressin MNC activity.
osmoregulation; oxytocin; paraventricular nucleus; reproduction; supraoptic nucleus; vasopressin.
© 2013 British Society for Neuroendocrinology.
Figure 1. Activity patterning in magnocellular neurosecretory cells
The ratemeter records show individual examples of the spontaneous activity (averaged in 1 s bins) of MNCs displaying each of the activity patterns typical of magnocellular neurosecretory cells (MNCs) in urethane anaesthetised rats. Under basal conditions, MNCs exhibit a range of activity patterns from silence (
A), through irregular activity ( B) to continuous activity ( C) and, in vasopressin MNCs only, phasic activity ( D). In A, action potentials were evoked in a silent MNC by electrical stimulation of the posterior pituitary gland every 30 s (evoked spikes). The recording in E is from an oxytocin MNC in a urethane-anesthetised rat being suckled during lactation and shows the typical high frequency bursts evident in oxytocin MNCs during parturition and suckling. The insets in E show the intramammary pressure increase for milk ejection that follows each burst of activity in the oxytocin MNC. Data for E was kindly provided by Prof J.A. Russell, University of Edinburgh.
Figure 2. The magnocellular neurosecretory system
A – C, Photomicrographs of coronal sections of rat hypothalamus ( A), in which vasopressin magnocellular neurosecretory cells (MNCs) are immunostained with fluorescent green and oxytocin MNCs with fluorescent red. MNC cell bodies are principally found in the hypothalamic supraoptic nucleus (SON) ( B), lateral to the optic chiasm (OC), and paraventricular nucleus (PVN) ( C), lateral to the third cerebral ventricle (3V). The SON contains only MNCs that project to the posterior pituitary gland, whereas the PVN also contains parvocellular oxytocin and vasopressin MNCs (as well as other parvocellular neurones) that project elsewhere in the brain. D, Photomicrograph of vasopressin axon terminals in the posterior pituitary gland. E, Electron micrograph showing MNC dendrites densely packed with dense-core vesicles (small black dots). We thank Dr Vicky Tobin, University of Edinburgh, for generation of the immunohistochemistry images.
Figure 3. Frequency facilitation of oxytocin and vasopressin release from magnocellular neurosecretory cells terminals
Isolated posterior pituitary glands were electrically stimulated with 156 pulses delivered at each of the four frequencies indicated in a balanced order of presentation. Evoked hormone release is expressed as a percentage of the total release evoked by the four stimulations. Note that hormone release is facilitated at higher frequencies, that little hormone is released at frequencies of < 4 Hz and that frequency facilitation of vasopressin release peaks at a lower frequency than for oxytocin release. Modified from (33), with permission.
Figure 4. Post-spike excitability and post-spike potentials in magnocellular neurosecretory cells
A and B, Schematic representations of inter-spike interval distribution of oxytocin ( A) magnocellular neurosecretory cells (MNCs) and vasopressin MNCs ( B). The tail of the distribution is fit by a single exponential decay (dashed line); for vasopressin MNCs, but not oxytocin MNCs, the exponential does not fit the peak of the distribution. C and D, Schematic representations of hazard functions for oxytocin MNCs ( C) and vasopressin MNCs ( D). Hazard functions are the probability of the next spike firing with time after the preceding spike and represent the post-spike excitability of neurones. Hazards are calculated from the inter-spike distributions using the formula: h = [i-1, i] n / ( [i-1, 1] N – n[0, i-1]), where h is the hazard at inter-spike interval i, [i-1, i] n is the number of spikes in inter-spike interval, i, [i-1, 1] n[0, i-1] is the total number of spikes preceding the current inter-spike interval and N is the total number of spikes in all inter-spike intervals. E and F, Schematic representations of individual spikes from an oxytocin MNC ( E) and a vasopressin MNC ( F), with the associated changes in membrane potential caused by the medium afterhyperpolarization (mAHP) and slow afterdepolarization (sADP) (not to scale). MNCs exhibit a prominent post-spike mAHP that initially hyperpolarises the cell after each spike, making it less likely to reach spike threshold (post-spike refractoriness). Vasopressin MNCs also exhibit a prominent post-spike sADP that is lower amplitude and longer-lasting than the mAHP; the sADP increases causes post-spike hyperexcitability by bringing the membrane potential closer to spike threshold, making it more likely that on-going (stochastic) synaptic input will reach spike threshold to trigger a further spike. If a spike does not fire, the probability of spike firing returns a steady-state hazard that is inferred to reflect the baseline membrane potential and the on-going synaptic input activity.
Figure 5. Priming somato-dendritic oxytocin release
Calcium influx triggers somato-dendritic oxytocin release (
A). Oxytocin activates oxytocin receptors on the plasma membrane to increase intracellular inositol triphosphate (IP3) concentrations ( B). IP3 increases calcium release from the endoplasmic reticulum ( C) to mobilise dense-core vesicles from the reserve pool to the readily-releasable pool ( D), ‘priming’ oxytocin MNCs to release increased amounts of oxytocin in response to subsequent stimuli.
Figure 6. Glial regulation of magnocellular neurosecretory cell activity under basal conditions
A, α1-adrenoreceptor (αAR) or group 1 and 5 metabotropic glutamate receptor (mGluR) activation increases intracellular calcium in astrocytes via inositol triphosphate (IP 3) to trigger ATP release. ATP activates magnocellular neurosecretory cell (MNC) P2X receptors (P2XR) to increase calcium influx, which activates phosphotidyl inositol 3-kinase (PI3K) to increase AMPA receptor (AMPAR) insertion into the postsynaptic membrane, mediating long-term potentiation of glutamate synapses (synaptic scaling). B, Astrocyte glutamate transporters (GLT-1) remove glutamate from the extracellular space to limit activation of extrasynaptic NMDA receptors (eNMDAR). C, Astrocytes release D-serine to act as a co-agonist with glutamate at postsynaptic NMDARs on MNCs. D, Astrocytes release taurine through volume-regulated anion channels (VRA) to activate extrasynaptic glycine receptors (GlyR) to hyperpolarise the MNC via chloride influx.
Figure 7. Integrated physiological modulation of magnocellular neurosecretory cell activity
Under basal conditions (top panel) various excitatory and inhibitory intrinsic, local and afferent mechanisms integrate to generate low frequency action potential discharge (
A) in magnocellular neurosecretory cells (MNC) to maintain relatively low and constant circulating oxytocin and vasopressin concentrations. Excitatory inputs, principally but not exclusively from glutamate neurones ( B) depolarise the MNC for a short time after each synaptic event; if threshold is reached, post-spike potentials (not shown) will modulate membrane potential. In parallel with excitatory drive, inhibitory inputs, principally but not exclusively from GABA neurones ( C) will transiently hyperpolarise the MNC. Astrocytes express glutamate transporter-1 (GLT-1), which prevents synaptically-released glutamate reaching metabotropic glutamate receptors (mGluR) on other afferent inputs ( D) and extrasynaptic NMDA receptors (NMDAR) on MNCs ( E). Astrocytes release D-Serine that acts as a co-agonist at NMDARs to permit glutamate activation ( F) and taurine that activates extrasynaptic glycine receptors to tonically hyperpolarise MNCs ( G). Some stretch-inactivated TRPV1 channels are active to tonically depolarise MNCs. Under stimulated conditions, each of these mechanisms is altered to increase the probability of action potential discharge ( I). Glutamate release is increased to increase EPSC frequency ( J). GABA release is also increased to increase IPSC frequency ( K) to dampen the gain of the excitatory drive. Withdrawal of astrocytic processes (glial retraction) reduces the physical barrier to neurotransmitter diffusion and reduces the efficacy of GLT-1 to allow spillover of glutamate to activate mGluR on neighbouring GABA synaptic terminals ( L), presumably to prevent over-inhibition. Glial retraction also allows glutamate to activate extrasynaptic NMDARs (eNMDAR) to induce a tonic depolarisation ( M). A further consequence of glial retraction is to reduce the efficacy of D-serine released from astrocytes ( N), presumably to limit excitation. When astrocytes shrink (e.g in hyperosmotic conditions), volume-regulated anion (VRA) channels close to reduce glycine release and reverse the tonic hyperpolarization mediated by GlyR ( O). MNC shrinkage opens TRPV1 channels to increase the tonic depolarisation. The net effect of these changes is to drive baseline membrane potential towards threshold and increase noise in the baseline membrane potential, increasing the probability that action potential threshold will be reached. See text for details of the specific physiological conditions that modulate each of the mechanisms.
Figure 8. Schematic representation of some of the major peripheral and afferent inputs to magnocellular neurosecretory cells
See text for details of the physiological functions of each of the inputs. Abbreviations: ARN: arcuate nucleus; BNST: bed nucleus of the stria terminalis; DBB: diagonal band of Broca; DRN: dorsal raphe nucleus; LC: locus coeruleus; MnPO: median preoptic nucleus; MRN: median raphe nucleus; NTS: nucleus tractus solitarius; OB: olfactory bulb; OVLT: organum vasculosum of the lamina terminalis; pcSN: pars compacta of the substantia nigra; PNZ: perinuclear zone; PPAH: preoptic periventricular /anterior hypothalamic region; SCN: suprachiasmatic nucleus; SFO: subfornical organ; TM: tuberomammillary nucleus; VLM: ventrolateral medulla; VTA: ventral tegmental area.
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