{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:21:37Z","timestamp":1772173297761,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011820","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000}}],"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["200551\/2022-1"],"award-info":[{"award-number":["200551\/2022-1"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["BB\/X005038\/1 and EP\/V048716\/1"],"award-info":[{"award-number":["BB\/X005038\/1 and EP\/V048716\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS 2324962"],"award-info":[{"award-number":["DMS 2324962"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The pulsatile activity of gonadotropin-releasing hormone neurons (GnRH neurons) is a key factor in the regulation of reproductive hormones. This pulsatility is orchestrated by a network of neurons that release the neurotransmitters kisspeptin, neurokinin B, and dynorphin (KNDy neurons), and produce episodic bursts of activity driving the GnRH neurons. We show in this computational study that the features of coordinated KNDy neuron activity can be explained by a neural network in which connectivity among neurons is modular. That is, a network structure consisting of clusters of highly-connected neurons with sparse coupling among the clusters. This modular structure, with distinct parameters for intracluster and intercluster coupling, also yields predictions for the differential effects on synchronization of changes in the coupling strength within clusters versus between clusters.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011820","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T16:06:49Z","timestamp":1722442009000},"page":"e1011820","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Population bursts in a modular neural network as a mechanism for synchronized activity in KNDy neurons"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2981-1291","authenticated-orcid":true,"given":"Wilfredo","family":"Blanco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Tabak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8577-2592","authenticated-orcid":true,"given":"Richard","family":"Bertram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"pcbi.1011820.ref001","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1016\/B978-012515400-0\/50048-8","volume-title":"Knobil and Neill\u2019s Physiology of Reproduction","author":"ME Freeman","year":"2006","edition":"3"},{"key":"pcbi.1011820.ref002","doi-asserted-by":"crossref","first-page":"7713","DOI":"10.1016\/S0021-9258(18)53015-5","article-title":"Mechanism of agonist-induced [Ca2+]i oscillations in pituitary gonadotrophs","volume":"268","author":"SS Stojilkovic","year":"1993","journal-title":"J Biol Chem"},{"key":"pcbi.1011820.ref003","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.tem.2005.03.003","article-title":"Biophysical basis of pituitary cell type-specific Ca2+ signaling-secretion coupling","volume":"16","author":"SS Stojilkovic","year":"2005","journal-title":"TRENDS Endocrin Metab"},{"key":"pcbi.1011820.ref004","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1210\/endo.130.1.1727719","article-title":"Dynamics of gonadotropin-releasing hormone release during a pulse","volume":"130","author":"SM Moenter","year":"1992","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref005","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1210\/endo-111-5-1449","article-title":"Simultaneous measurement of luteinizing hormone-releasing hormone and luteinizing hormone release in unanesthetized, ovariectomized sheep","volume":"111","author":"JE Levine","year":"1982","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref006","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1152\/jn.2001.86.1.86","article-title":"Long-term recordings of networks of immortalized GnRH neurons reveal episodic patterns of electrical activity","volume":"86","author":"CS Nunemaker","year":"2001","journal-title":"J Neurophysiol"},{"key":"pcbi.1011820.ref007","doi-asserted-by":"crossref","first-page":"3731","DOI":"10.1210\/endo.141.10.7690","article-title":"Whole-cell recordings from preoptic\/hypothalamic slices reveal burst firing in gonadotropin-releasing hormone neurons identified with green fluorescent protein in transgenic mice","volume":"141","author":"KJ Suter","year":"2000","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref008","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1126\/science.100883","article-title":"Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone","volume":"202","author":"PE Belchetz","year":"1978","journal-title":"Science"},{"key":"pcbi.1011820.ref009","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1210\/endo-109-2-376","article-title":"Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey","volume":"109","author":"L Wildt","year":"1981","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref010","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1056\/NEJMoa035322","article-title":"The GPR54 gene as a regulator of puberty","volume":"349","author":"SB Seminara","year":"2003","journal-title":"N Engl J Med"},{"key":"pcbi.1011820.ref011","doi-asserted-by":"crossref","first-page":"10972","DOI":"10.1073\/pnas.1834399100","article-title":"Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54","volume":"100","author":"N de Roux","year":"2003","journal-title":"Proc Nat Acad Sci"},{"key":"pcbi.1011820.ref012","doi-asserted-by":"crossref","first-page":"5752","DOI":"10.1210\/en.2007-0961","article-title":"Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B","volume":"148","author":"RL Goodman","year":"2007","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref013","doi-asserted-by":"crossref","first-page":"4259","DOI":"10.1210\/en.2013-1331","article-title":"Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes","volume":"154","author":"RL Goodman","year":"2013","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref014","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1073\/pnas.0409330102","article-title":"Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54","volume":"102","author":"S Messager","year":"2005","journal-title":"Proc Nat Acad Sci"},{"key":"pcbi.1011820.ref015","doi-asserted-by":"crossref","first-page":"E10216","DOI":"10.1073\/pnas.1713897114","article-title":"Definition of the hypothalamic GnRH pulse generator in mice","volume":"114","author":"J Clarkson","year":"2017","journal-title":"Proc Nat Acad Sci"},{"key":"pcbi.1011820.ref016","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1210\/en.2018-00653","article-title":"The Gonadotropin-releasing hormone pulse generator","volume":"159","author":"AE Herbison","year":"2018","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref017","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1210\/en.2018-00389","article-title":"KNDy cells revisited","volume":"159","author":"AM Moore","year":"2018","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref018","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2021.724632","article-title":"Role of KNDy neurons expressing kisspeptin, neurokinin B, and dynorphin A as a GnRH pulse generator controlling mammalian reproduction","volume":"12","author":"Y Uenoyama","year":"2021","journal-title":"Front Endocrinol"},{"key":"pcbi.1011820.ref019","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1210\/en.2010-0022","article-title":"Minireview: kisspeptin\/neurokinin B\/dynorphin (KNDy) cells of the arcuate nucleus: A central node in the control of gonadotropin-releasing hormone secretion","volume":"151","author":"MN Lehman","year":"2010","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref020","doi-asserted-by":"crossref","first-page":"11859","DOI":"10.1523\/JNEUROSCI.1569-09.2009","article-title":"Regulation of gonadotropin-releasing hormone secretion by kisspeptin\/dynorphin\/neurokinin B neurons in the arcuate nucleus of the mouse","volume":"29","author":"VM Navarro","year":"2009","journal-title":"J Neurosci"},{"key":"pcbi.1011820.ref021","doi-asserted-by":"crossref","first-page":"9738","DOI":"10.1523\/JNEUROSCI.0828-19.2019","article-title":"The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach","volume":"39","author":"M Voliotis","year":"2019","journal-title":"J Neurosci"},{"key":"pcbi.1011820.ref022","first-page":"11914","article-title":"Mechanism of kisspeptin neuron synchronization for pulsatile hormone secretion in male mice","volume":"42","author":"SY Han","year":"2023","journal-title":"Cell Rep"},{"key":"pcbi.1011820.ref023","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqad167","article-title":"Mechanism of arcuate kisspeptin neuron synchronization in acute brain slices from female mice","volume":"164","author":"PG Morris","year":"2023","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref024","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1523\/JNEUROSCI.2428-17.2017","article-title":"Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor alpha in adult female mice","volume":"38","author":"L Wang","year":"2018","journal-title":"J Neurosci"},{"key":"pcbi.1011820.ref025","doi-asserted-by":"crossref","first-page":"e35656","DOI":"10.7554\/eLife.35656","article-title":"Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females","volume":"7","author":"J Qiu","year":"2018","journal-title":"eLife"},{"key":"pcbi.1011820.ref026","doi-asserted-by":"crossref","first-page":"e2117767119","DOI":"10.1073\/pnas.2117767119","article-title":"In vivo imaging of the GnRH pulse generator reveals a temporal order of neuronal activation and synchronization during each pulse","volume":"119","author":"AM Moore","year":"2023","journal-title":"Proc Nat Acad Sci"},{"key":"pcbi.1011820.ref027","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1152\/jn.00857.2009","article-title":"Mechanism for the universal pattern of activity in developing neuronal networks","volume":"103","author":"J Tabak","year":"2010","journal-title":"J Neurophysiol"},{"key":"pcbi.1011820.ref028","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fncom.2017.00088","article-title":"The effects of GABAergic polarity changes on episodic neural network activity in developing neural systems","volume":"11","author":"W Blanco","year":"2017","journal-title":"Front Comput Neurosci"},{"issue":"3","key":"pcbi.1011820.ref029","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s10827-020-00748-3","article-title":"Non-replicability circumstances in a neural network model with Hodgkin-Huxley-type neurons","volume":"48","author":"W Blanco","year":"2020","journal-title":"J Comput Neurosci"},{"key":"pcbi.1011820.ref030","doi-asserted-by":"crossref","DOI":"10.3389\/fninf.2022.874234","article-title":"Mitigating computer limitations in replicating numerical simulations of a neural network model with Hodgkin-Huxley-type neurons","volume":"16","author":"PH Lopes","year":"2022","journal-title":"Front Neuroinform"},{"key":"pcbi.1011820.ref031","first-page":"2944","article-title":"Excitation dynamics: insights from simplified membrane models","volume":"44","author":"J Rinzel","year":"1985","journal-title":"Fed Proc"},{"key":"pcbi.1011820.ref032","doi-asserted-by":"crossref","unstructured":"Bastian M, Heymann S, Jacomy M. Gephi: An Open Source Software for Exploring and Manipulating Networks; 2009. Available from: www.aaai.org\/ocs\/index.php\/ICWSM\/09\/paper\/view\/154.","DOI":"10.1609\/icwsm.v3i1.13937"},{"key":"pcbi.1011820.ref033","doi-asserted-by":"crossref","first-page":"8966","DOI":"10.1523\/JNEUROSCI.21-22-08966.2001","article-title":"The role of activity-dependent network depression in the expression and self-regulation of spontaneous activity in the developing spinal cord","volume":"21","author":"J Tabak","year":"2001","journal-title":"J Neurosci"},{"key":"pcbi.1011820.ref034","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1210\/en.2013-1231","article-title":"Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse","volume":"154","author":"S de Croft","year":"2013","journal-title":"Endocrinology"},{"key":"pcbi.1011820.ref035","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.neulet.2015.12.008","article-title":"Immunoelectron microscopic observation of the subcellular localization of kisspeptin, neurokinin B and dynorphin A in KNDy neurons in the arcuate nucleus of the female rat","volume":"612","author":"H Murakawa","year":"2016","journal-title":"Neurosci Lett"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011820","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011820","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T13:38:29Z","timestamp":1723469909000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011820"}},"subtitle":[],"editor":[{"given":"Jonathan David","family":"Touboul","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011820","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.01.12.575324","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,31]]}}}