60 YEARS OF NEUROENDOCRINOLOGY: The posterior pituitary, from Geoffrey Harris to our present understanding
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Figure 1
(A) Harris and co-workers showed that electrical stimulation of the neural stalk in lactating rabbits resulted in a sharp rise in intramammary pressure, and they inferred that this was the consequence of oxytocin secreted from the posterior pituitary. They noted that the response to stimulation depended strongly on the frequency of stimulation. The explanation for this has two components. First, the response of the mammary gland to oxytocin is non-linear . Reproduced, with permission from The Physiological Society, from Harris GW, Manabe Y & Ruf KB (1969) A study of the parameters of electrical stimulation of unmyelinated fibres in the pituitary stalk. Journal of Physiology 203 67–81. Copyright 1969 The Physiological Society. (B) The rabbit mammary gland shows a threshold response to i.v. injection of 10 mU oxytocin and a near-maximal response to a dose of 50 mU. Second, the secretion of oxytocin is greatly facilitated by increasing the frequency of stimulation. Reproduced, with permission, from Cross BA & Harris GW (1952) The role of the neurohypophysis in the milk ejection reflex. Journal of Endocrinology 8 148–161. (C) The amount of oxytocin (and vasopressin) that is released from the rat posterior pituitary gland in vitro in response to a fixed number of electrical stimulus pulses varies markedly with the frequency at which the pulses are applied (the graph plots hormone release in response to 156 pulses at each frequency). Reproduced, with permission, from Bicknell RJ (1988) Optimizing release from peptide hormone secretory nerve terminals. Journal of Experimental Biology 139 51–65. Copyright 1988 The Company of Biologists Limited. (D) During the milk-ejection reflex (MER), oxytocin neurons discharge short bursts (1–3 s) at a spike frequency that averages 40–50 spikes/s (i.e. at a frequency that optimises the efficiency of secretion and that evokes a sharp rise in intramammary pressure). Reproduced, with permission from The Physiological Society, from Lincoln DW & Wakerley JB (1974) Electrophysiological evidence for the activation of supraoptic neurones during the release of oxytocin. Journal of Physiology 242 533–554. Copyright 1974 The Physiological Society. (E) This response is indeed attributable to a pulse of oxytocin, as measured in the blood by RIA. Reproduced, with permission, from Higuchi T, Honda K, Fukuoka T, Negoro H & Wakabayashi K (1985) Release of oxytocin during suckling and parturition in the rat. Journal of Endocrinology 105 339–346. As shown in (F), similar bursts are observed during parturition. Reproduced, with permission, from Summerlee AJ, Paisley AC, O'Byrne KT, Fairhall KM, Robinson IC & Fletcher J (1986) Aspects of the neuronal and endocrine components of reflex milk ejection in conscious rabbits. Journal of Endocrinology 108 143–149.
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Figure 2
(A) Vasopressin and oxytocin that circulate in the plasma are synthesised by magnocellular neurons whose cell bodies are located mainly in the paraventricular (PVN) and the supraoptic nuclei (SON) of the hypothalamus (vasopressin cells are immunostained with fluorescent green and oxytocin cells with fluorescent red). (B) The peptide immunostaining is punctate and represents individual or aggregates of large dense-cored vesicles, and in dendrites, the vesicles are particularly abundant.
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Figure 3
(A) Push–pull perfusion studies have shown that dendritic oxytocin release increases before the high-frequency burst activity of oxytocin neurons which is associated with the milk-ejection reflex. Reproduced, with permission, from Moos F, Poulain DA, Rodriguez F, Guerne Y, Vincent JD & Richard P (1989) Release of oxytocin within the supraoptic nucleus during the milk rejection reflex in rats. Experimental Brain Research 76 593–602. Copyright 1989 Springer-Verlag. (B) The i.c.v. injection of oxytocin increases the burst amplitude and the burst frequency of oxytocin cells, which shows that central release regulates the milk-ejection reflex. Reproduced, with permission, from Brown D, Fontanaud P & Moos FC (2000) The variability of basal action potential firing is positively correlated with bursting in hypothalamic oxytocin neurones. Journal of Neuroendocrinology 12 506–520. Copyright 2000 Blackwell Science Ltd. (C) Dendritic oxytocin release can be conditionally primed. Reproduced, with permission, from Ludwig M & Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nature Reviews Neuroscience 7 126–136. Copyright 2006, Rights Managed by Nature Publishing Group. (D) Under normal conditions, dendritic peptide release is not activated by electrical (spike) activity. This is indicated by the lack of dendritic oxytocin release in response to electrical stimulation of the neural stalk (light grey columns). (E) A conditional signal (arrow), such as oxytocin itself, triggers release from dendrites independently of the electrical activity. Reproduced, with permission, from Ludwig M, Sabatier N, Bull PM, Landgraf R, Dayanithi G & Leng G (2002) Intracellular calcium stores regulate activity-dependent neuropeptide release from dendrites. Nature 418 85–89. Copyright 2002, Rights Managed by Nature Publishing Group. (F) The conditional signal also primes dendritic stores. Priming occurs partially by the relocation of dendritic large dense-core vesicles closer to the dendritic plasma membrane. Reproduced, with permission, from Tobin VA, Hurst G, Norrie L, Dal Rio FP, Bull PM & Ludwig M (2004) Thapsigargin-induced mobilization of dendritic densecored vesicles in rat supraoptic neurons. European Journal of Neuroscience 19 2909–2912. Copyright 2004 Federation of European Neuroscience Societies. (G) After oxytocin-induced priming, the vesicles are available for activity-dependent release for a prolonged period. Reproduced, with permission, from Ludwig M, Sabatier N, Bull PM, Landgraf R, Dayanithi G & Leng G (2002) Intracellular calcium stores regulate activity-dependent neuropeptide release from dendrites. Nature 418 85–89. Copyright 2002, Rights Managed by Nature Publishing Group.
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