{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:51:32Z","timestamp":1791571892329,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014832","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/S021035\/1"],"award-info":[{"award-number":["BB\/S021035\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Hypothalamic vasopressin neurons are neuroendocrine cells which form part of the homeostatic systems that regulate plasma volume and extracellular fluid osmolarity. In response to synaptic inputs encoding osmolarity and changes in plasma volume, they generate complex and dynamically heterogeneous patterns of spikes that in turn trigger secretion of peptide hormone vasopressin from axonal terminals in the posterior pituitary. The thousands of neurons\u2019 secretory signals generate a summed plasma vasopressin signal acting at the kidneys to regulate water loss. Vasopressin is synthesised in the neuronal cell bodies, packaged into vesicles, and transported to large stores at the pituitary terminals. Supported by activity-dependent upregulation of synthesis and transport, these stores can maintain a secretion response for several days of elevated osmolarity, experimentally tested by dehydration or salt loading. However, despite upregulated synthesis, stores gradually decline during sustained challenge, followed by a slow recovery. With no evidence of a store encoding feedback signal, previous simple modelling explained these synthesis dynamics based on activity-dependent upregulation of transcription and mRNA content. Here we integrate this idea into a detailed neuronal model, coupling spiking, secretion, and synthesis to simulate a complete neural system, from physiological input to output, and ask how a distributed neuroendocrine system can maintain hormone supply-demand balance over prolonged challenge without direct feedback from distant hormone stores. The model suggests that mRNA acts as a long-timescale memory of neuronal activity, extending temporal integration beyond spike activity and intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    to coordinate synthesis with sustained demand.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014832","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:42:31Z","timestamp":1790790151000},"page":"e1014832","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modelling vasopressin synthesis and storage dynamics during prolonged osmotic challenge and recovery based on activity dependent upregulation of mRNA transcription"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3046-6640","authenticated-orcid":true,"given":"Duncan J.","family":"MacGregor","sequence":"first","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"22","key":"pcbi.1014832.ref001","doi-asserted-by":"crossref","first-page":"7089","DOI":"10.1113\/JP288860","article-title":"Reduced osmoresponsiveness in magnocellular neuroendocrine neurones during chronic salt-loading","volume":"603","author":"M Lozic","year":"2025","journal-title":"J Physiol"},{"issue":"10","key":"pcbi.1014832.ref002","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1002740","article-title":"Phasic firing in vasopressin cells: understanding its functional significance through computational models","volume":"8","author":"DJ MacGregor","year":"2012","journal-title":"PLoS Comput Biol"},{"issue":"8","key":"pcbi.1014832.ref003","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1003187","article-title":"Spike triggered hormone secretion in vasopressin cells; a model investigation of mechanism and heterogeneous population function","volume":"9","author":"DJ MacGregor","year":"2013","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"pcbi.1014832.ref004","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/ki.1976.76","article-title":"The osmoregulation of vasopressin","volume":"10","author":"GL Robertson","year":"1976","journal-title":"Kidney Int"},{"key":"pcbi.1014832.ref005","article-title":"Osmotic regulation of plasma vasopressin and oxytocin after sustained hyponatremia","volume":"250","author":"JG Verbalis","year":"1986","journal-title":"Am J Physiol"},{"key":"pcbi.1014832.ref006","doi-asserted-by":"crossref","first-page":"5625","DOI":"10.1113\/jphysiol.2008.159103","article-title":"Neurotransmitters and peptides: whispered secrets and public announcements","volume":"586","author":"G Leng","year":"2008","journal-title":"J Physiol"},{"issue":"2","key":"pcbi.1014832.ref007","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1113\/jphysiol.1972.sp010047","article-title":"Intra-axonal transport and turnover of neurohypophysial hormones in the rat","volume":"227","author":"CW Jones","year":"1972","journal-title":"J Physiol"},{"issue":"2","key":"pcbi.1014832.ref008","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.biosystems.2013.03.010","article-title":"Information coding in vasopressin neurons--the role of asynchronous bistable burst firing","volume":"112","author":"DJ MacGregor","year":"2013","journal-title":"Biosystems"},{"key":"pcbi.1014832.ref009","article-title":"Changes in the hormone content of the rat neurohypophysis induced by substituting 2 per cent saline for drinking water","volume":"43","author":"CW Jones","year":"1969","journal-title":"J Endocrinol"},{"issue":"3","key":"pcbi.1014832.ref010","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1677\/joe.0.0400337","article-title":"Repletion of vasopressin and oxytocin in the posterior lobe of the pituitary gland of the rat","volume":"40","author":"TK Young","year":"1968","journal-title":"J Endocrinol"},{"issue":"6","key":"pcbi.1014832.ref011","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1523\/JNEUROSCI.06-06-01685.1986","article-title":"Vasopressin mRNA regulation in individual hypothalamic nuclei: A northern and in situ hybridization analysis","volume":"6","author":"TG Sherman","year":"1986","journal-title":"J Neurosci"},{"key":"pcbi.1014832.ref012","article-title":"Total translation of vasopressin and oxytocin in neurohypophysis of rats","volume":"257","author":"AG Robinson","year":"1989","journal-title":"Am J Physiol"},{"key":"pcbi.1014832.ref013","article-title":"Models of neurohypophyseal homeostasis","volume":"262","author":"MD Fitzsimmons","year":"1992","journal-title":"Am J Physiol"},{"key":"pcbi.1014832.ref014","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0167-0115(93)90210-Y","article-title":"Vasopressin homeostasis: coordination of synthesis, storage and release","volume":"45","author":"AG Robinson","year":"1993","journal-title":"Regul Pept"},{"issue":"28","key":"pcbi.1014832.ref015","doi-asserted-by":"crossref","first-page":"12956","DOI":"10.1016\/S0021-9258(18)69255-5","article-title":"Regulation of vasopressin gene expression in rat hypothalamic neurons. Response to osmotic stimulation","volume":"261","author":"HH Zingg","year":"1986","journal-title":"J Biol Chem"},{"issue":"4","key":"pcbi.1014832.ref016","first-page":"416","article-title":"Vasopressin transport regulation is coupled to the synthesis rate","volume":"53","author":"MM Roberts","year":"1991","journal-title":"Neuroendocrinology"},{"issue":"1","key":"pcbi.1014832.ref017","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0014-5793(95)01008-3","article-title":"Effect of hypoosmolality on the abundance, poly(A) tail length and axonal targeting of arginine vasopressin and oxytocin mRNAs in rat hypothalamic magnocellular neurons","volume":"373","author":"PC Svane","year":"1995","journal-title":"FEBS Lett"},{"issue":"6","key":"pcbi.1014832.ref018","first-page":"2267","article-title":"The vasopressin mRNA poly(A) tract is unusually long and increases during stimulation of vasopressin gene expression in vivo","volume":"8","author":"EJ Carrazana","year":"1988","journal-title":"Mol Cell Biol"},{"issue":"23","key":"pcbi.1014832.ref019","doi-asserted-by":"crossref","first-page":"11041","DOI":"10.1016\/S0021-9258(18)37914-6","article-title":"Regulation of poly(A) tail size of vasopressin mRNA","volume":"263","author":"HH Zingg","year":"1988","journal-title":"J Biol Chem"},{"issue":"6","key":"pcbi.1014832.ref020","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1210\/endo.139.6.6043","article-title":"Vasopressin messenger ribonucleic acid regulation via the protein kinase A pathway","volume":"139","author":"RL Emanuel","year":"1998","journal-title":"Endocrinology"},{"issue":"2","key":"pcbi.1014832.ref021","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/0006-8993(89)90839-1","article-title":"Cyclic nucleotide dynamics in the rat hypothalamus during osmotic stimulation: in vivo and in vitro studies","volume":"487","author":"DA Carter","year":"1989","journal-title":"Brain Res"},{"key":"pcbi.1014832.ref022","article-title":"cAMP regulation of vasopressin mRNA content in hypothalamo-neurohypophysial explants","volume":"271","author":"CD Sladek","year":"1996","journal-title":"Am J Physiol"},{"issue":"1","key":"pcbi.1014832.ref023","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S1044-7431(03)00123-4","article-title":"cAMP-dependent protein kinase A mediation of vasopressin gene expression in the hypothalamus of the osmotically challenged rat","volume":"24","author":"L-F Wong","year":"2003","journal-title":"Mol Cell Neurosci"},{"issue":"1","key":"pcbi.1014832.ref024","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13041-015-0159-1","article-title":"Transcription factor CREB3L1 mediates cAMP and glucocorticoid regulation of arginine vasopressin gene transcription in the rat hypothalamus","volume":"8","author":"M Greenwood","year":"2015","journal-title":"Mol Brain"},{"key":"pcbi.1014832.ref025","doi-asserted-by":"crossref","first-page":"146357","DOI":"10.1016\/j.brainres.2019.146357","article-title":"NMDA receptor-dependent signalling pathways regulate arginine vasopressin expression in the paraventricular nucleus of the rat","volume":"1722","author":"D Lake","year":"2019","journal-title":"Brain Res"},{"issue":"3","key":"pcbi.1014832.ref026","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1210\/en.2017-03068","article-title":"A Predictive, Quantitative Model of Spiking Activity and Stimulus-Secretion Coupling in Oxytocin Neurons","volume":"159","author":"J Ma\u00edcas-Royo","year":"2018","journal-title":"Endocrinology"},{"issue":"5","key":"pcbi.1014832.ref027","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/0031-9384(74)90237-6","article-title":"Supraoptic neuronal activity in rats during five days of water deprivation","volume":"13","author":"JK Walters","year":"1974","journal-title":"Physiol Behav"},{"issue":"1","key":"pcbi.1014832.ref028","first-page":"25","article-title":"Hormone content and movement of neurosecretory granules in the rat neural lobe during and after dehydration","volume":"40","author":"JJ Nordmann","year":"1985","journal-title":"Neuroendocrinology"},{"issue":"2","key":"pcbi.1014832.ref029","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1365-2826.2007.01640.x","article-title":"Differential kinetics of oxytocin and vasopressin heteronuclear RNA expression in the rat supraoptic nucleus in response to chronic salt loading in vivo","volume":"20","author":"C Yue","year":"2008","journal-title":"J Neuroendocrinol"},{"issue":"2","key":"pcbi.1014832.ref030","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0006-8993(81)90341-3","article-title":"Time course of appearance and release of [35S]cysteine labelled neurophysins and peptides in the neurohypophysis","volume":"205","author":"JT Russell","year":"1981","journal-title":"Brain Res"},{"key":"pcbi.1014832.ref031","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1113\/jphysiol.1995.sp020674","article-title":"Regulation of spontaneous phasic firing of rat supraoptic vasopressin neurones in vivo by glutamate receptors","author":"R Nissen","year":"1995","journal-title":"J Physiol"},{"key":"pcbi.1014832.ref032","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1113\/jphysiol.2003.058842","article-title":"Kinetics of Mg2+ unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity","volume":"556","author":"BM Kampa","year":"2004","journal-title":"J Physiol"},{"issue":"5","key":"pcbi.1014832.ref033","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1523\/JNEUROSCI.18-05-01879.1998","article-title":"Vasopressin regularizes the phasic firing pattern of rat hypothalamic magnocellular vasopressin neurons","volume":"18","author":"L Gouz\u00e8nes","year":"1998","journal-title":"J Neurosci"},{"issue":"5","key":"pcbi.1014832.ref034","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1365-2826.2010.01961.x","article-title":"State-dependent plasticity in vasopressin neurones: dehydration-induced changes in activity patterning","volume":"22","author":"V Scott","year":"2010","journal-title":"J Neuroendocrinol"},{"issue":"8","key":"pcbi.1014832.ref035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0104802","article-title":"Salt appetite is reduced by a single experience of drinking hypertonic saline in the adult rat","volume":"9","author":"MP Greenwood","year":"2014","journal-title":"PLoS One"},{"issue":"14","key":"pcbi.1014832.ref036","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1113\/JP278045","article-title":"The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model","volume":"597","author":"J Ma\u00edcas Royo","year":"2019","journal-title":"J Physiol"},{"issue":"4","key":"pcbi.1014832.ref037","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nn.2503","article-title":"Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep","volume":"13","author":"E Trudel","year":"2010","journal-title":"Nat Neurosci"},{"issue":"4","key":"pcbi.1014832.ref038","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/j.1365-2826.2012.02298.x","article-title":"Circadian modulation of osmoregulated firing in rat supraoptic nucleus neurones","volume":"24","author":"E Trudel","year":"2012","journal-title":"J Neuroendocrinol"},{"issue":"2","key":"pcbi.1014832.ref039","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1677\/joe.0.1330283","article-title":"Daily rhythms in the hormone content of the neurohypophysial system and release of oxytocin and vasopressin in the male rat: effect of constant light","volume":"133","author":"RJ Windle","year":"1992","journal-title":"J Endocrinol"},{"issue":"2","key":"pcbi.1014832.ref040","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S0006-8993(00)03050-X","article-title":"Daily profiles of arginine vasopressin mRNA in the suprachiasmatic, supraoptic and paraventricular nuclei of the rat hypothalamus under various photoperiods","volume":"887","author":"M J\u00e1c","year":"2000","journal-title":"Brain Res"},{"key":"pcbi.1014832.ref041","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1113\/jphysiol.2004.063982","article-title":"Phasic spike patterning in rat supraoptic neurones in vivo and in vitro","volume":"558","author":"N Sabatier","year":"2004","journal-title":"J Physiol"},{"key":"pcbi.1014832.ref042","article-title":"Oxytocin neurones: intrinsic mechanisms governing the regularity of spiking activity","author":"J Ma\u00edcas Royo","year":"2016","journal-title":"J Neuroendocrinol"},{"issue":"17","key":"pcbi.1014832.ref043","doi-asserted-by":"crossref","first-page":"6967","DOI":"10.1523\/JNEUROSCI.21-17-06967.2001","article-title":"Responses of magnocellular neurons to osmotic stimulation involves coactivation of excitatory and inhibitory input: an experimental and theoretical analysis","volume":"21","author":"G Leng","year":"2001","journal-title":"J Neurosci"},{"issue":"7","key":"pcbi.1014832.ref044","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0180368","article-title":"Spike patterning in oxytocin neurons: Capturing physiological behaviour with Hodgkin-Huxley and integrate-and-fire models","volume":"12","author":"T Leng","year":"2017","journal-title":"PLoS One"},{"issue":"3","key":"pcbi.1014832.ref045","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1476-5381.1959.tb00252.x","article-title":"The fate of oxytocin in male and female rats","volume":"14","author":"M Ginsburg","year":"1959","journal-title":"Br J Pharmacol Chemother"},{"issue":"2","key":"pcbi.1014832.ref046","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1677\/joe.0.0430175","article-title":"The release, clearance and plasma protein binding of oxytocin in the anaesthetized rat","volume":"43","author":"M Fabian","year":"1969","journal-title":"J Endocrinol"},{"issue":"2","key":"pcbi.1014832.ref047","first-page":"108","article-title":"Evidence for the release of vasopressin and oxytocin into cerebrospinal fluid: measurements in plasma and CSF of intact and hypophysectomized rats","volume":"24","author":"J Dogterom","year":"1977","journal-title":"Neuroendocrinology"},{"issue":"2","key":"pcbi.1014832.ref048","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1677\/joe.0.1370311","article-title":"Patterns of neurohypophysial hormone release during dehydration in the rat","volume":"137","author":"RJ Windle","year":"1993","journal-title":"J Endocrinol"},{"issue":"3","key":"pcbi.1014832.ref049","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1677\/joe.0.0090283","article-title":"The clearance of injected vasopressin from the circulation and its fate in the body","volume":"9","author":"M Ginsburg","year":"1953","journal-title":"J Endocrinol"},{"issue":"8","key":"pcbi.1014832.ref050","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1172\/JCI105040","article-title":"The effect of various states of hydration and the plasma concentration on the turnover of antidiuretic hormone in mammals","volume":"43","author":"JW Czaczkes","year":"1964","journal-title":"J Clin Invest"},{"issue":"3","key":"pcbi.1014832.ref051","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1177\/0748730408316796","article-title":"A physiological model of a circannual oscillator","volume":"23","author":"DJ Macgregor","year":"2008","journal-title":"J Biol Rhythms"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1014832","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014832","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:06:56Z","timestamp":1791569216000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014832"}},"subtitle":[],"editor":[{"given":"Kim T.","family":"Blackwell","sequence":"first","affiliation":[{"name":"The University of Iowa College of Engineering","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":51,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1014832","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]}}}