{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:26:35Z","timestamp":1783571195830,"version":"3.55.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T00:00:00Z","timestamp":1652745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/S000550\/1"],"award-info":[{"award-number":["BB\/S000550\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020643","name":"Medical Research Centre","doi-asserted-by":"publisher","award":["MR\/N022637\/1"],"award-info":[{"award-number":["MR\/N022637\/1"]}],"id":[{"id":"10.13039\/501100020643","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Post-traumatic stress disorder impedes pubertal development and disrupts pulsatile LH secretion in humans and rodents. The posterodorsal sub-nucleus of the medial amygdala (MePD) is an upstream modulator of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator, pubertal timing, as well as emotional processing and anxiety. Psychosocial stress exposure alters neuronal activity within the MePD increasing the expression of Urocortin3 (Ucn3) and its receptor corticotropin-releasing factor type-2 receptor (CRFR2) while enhancing the inhibitory output from the MePD to key hypothalamic reproductive centres. We test the hypothesis that psychosocial stress, processed by the MePD, is relayed to the hypothalamic GnRH pulse generator to delay puberty in female mice. We exposed C57Bl6\/J female mice to the predator odor, 2,4,5-Trimethylthiazole (TMT), during pubertal transition and examined the effect on pubertal timing, pre-pubertal LH pulses and anxiety-like behaviour. Subsequently, we virally infected Ucn3-cre-tdTomato female mice with stimulatory DREADDs targeting MePD Ucn3 neurons and determined the effect on pubertal timing and pre-pubertal LH pulse frequency. Exposure to TMT during pubertal development delayed puberty, suppressed pre-pubertal LH pulsatility and enhanced anxiety-like behaviour, while activation of MePD Ucn3 neurons reduced LH pulse frequency and delayed puberty. Early psychosocial stress exposure decreases GnRH pulse generator frequency delaying puberty while inducing anxiety-behaviour in female mice, an effect potentially involving Ucn3 neurons in the MePD.<\/jats:p>","DOI":"10.3389\/fendo.2022.893029","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T07:55:11Z","timestamp":1652774111000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Role of Posterodorsal Medial Amygdala Urocortin-3 in Pubertal Timing in Female Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Deyana","family":"Ivanova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiaoFeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"McIntyre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geffen","family":"Lass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingsi","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin T.","family":"O\u2019Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"B1","article-title":"Effects of Stress After Hurricanes Katrina and Rita on Pubertal Disorders in Children","volume":"8","author":"Ponnapakkam","year":"2008","journal-title":"Ochsner J"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2019.0943","article-title":"Burden of Environmental Adversity Associated With Psychopathology, Maturation, and Brain Behavior Parameters in Youths","volume":"76","author":"Gur","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2016.06.003","article-title":"Predator-Based Psychosocial Stress Animal Model of PTSD: Preclinical Assessment of Traumatic Stress at Cognitive, Hormonal, Pharmacological, Cardiovascular and Epigenetic Levels of Analysis","volume":"284","author":"Zoladz","year":"2016","journal-title":"Exp Neurol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e12719","DOI":"10.1111\/jne.12719","article-title":"Role of the Posterodorsal Medial Amygdala in Predator Odour Stress-Induced Puberty Delay in Female Rats","volume":"31","author":"Li","year":"2019","journal-title":"J Neuroendocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab206","article-title":"Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-Induced Suppression of LH Pulsatility in Female Mice","volume":"162","author":"Ivanova","year":"2021","journal-title":"Endocrinology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00341","article-title":"Exposure to Acute Psychosocial Stress Disrupts the Luteinizing Hormone Surge Independent of Estrous Cycle Alterations in Female Mice","volume":"158","author":"Wagenmaker","year":"2017","journal-title":"Endocrinology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-6199-9_12","article-title":"Kisspeptin and Puberty in Mammals","volume":"784","author":"Terasawa","year":"2013","journal-title":"Adv Exp Med Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1834399100","article-title":"Hypogonadotropic Hypogonadism Due to Loss of Function of the KiSS1-Derived Peptide Receptor Gpr54","volume":"100","author":"De Roux","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa035322","article-title":"The GPR54 Gene as a Regulator of Puberty","volume":"349","author":"Seminara","year":"2003","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-1261","article-title":"Repetitive Activation of Hypothalamic G Protein-Coupled Receptor 54 With Intravenous Pulses of Kisspeptin in the Juvenile Monkey (Macaca Mulatta) Elicits a Sustained Train of Gonadotropin-Releasing Hormone Discharges","volume":"147","author":"Plant","year":"2006","journal-title":"Endocrinology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.072298","article-title":"Advanced Vaginal Opening and Precocious Activation of the Reproductive Axis by KiSS-1 Peptide, the Endogenous Ligand of GPR54","volume":"561","author":"Navarro","year":"2004","journal-title":"J Physiol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713897114","article-title":"Definition of the Hypothalamic GnRH Pulse Generator in Mice","volume":"114","author":"Clarkson","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e16246","DOI":"10.7554\/eLife.16246","article-title":"High-Frequency Stimulation-Induced Peptide Release Synchronizes Arcuate Kisspeptin Neurons and Excites GnRH Neurons","volume":"5","author":"Qiu","year":"2016","journal-title":"Elife"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0828-19.2019","article-title":"The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach","volume":"39","author":"Voliotis","year":"2019","journal-title":"J Neurosci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e62455","DOI":"10.7554\/ELIFE.62455","article-title":"Highly Redundant Neuropeptide Volume Co-Transmission Underlying Episodic Activation of the Gnrh Neuron Dendron","volume":"10","author":"Liu","year":"2021","journal-title":"Elife"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1159\/000503006","article-title":"Differential Roles of Hypothalamic AVPV and Arcuate Kisspeptin Neurons in Estradiol Feedback Regulation of Female Reproduction","volume":"110","author":"Wang","year":"2020","journal-title":"Neuroendocrinology"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2014.09.028","article-title":"Neonatal Amygdala Lesions Advance Pubertal Timing in Female Rhesus Macaques","volume":"51","author":"Stephens","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1966.211.5.1103","article-title":"Delayed Puberty Following Electrical Stimulation of Amygdala in Female Rats","volume":"211","author":"Bar-Sela","year":"1966","journal-title":"Am J Physiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1366","article-title":"The Posterodorsal Medial Amygdala Regulates the Timing of Puberty Onset in Female Rats","volume":"156","author":"Li","year":"2015","journal-title":"Endocrinology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.04.011","article-title":"Lhx6 Delineates a Pathway Mediating Innate Reproductive Behaviors From the Amygdala to the Hypothalamus","volume":"46","author":"Choi","year":"2005","journal-title":"Neuron"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1176-14.2014","article-title":"Functional Properties and Projections of Neurons in the Medial Amygdala","volume":"34","author":"Keshavarzi","year":"2014","journal-title":"J Neurosci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-019-51201-0","article-title":"Kisspeptin\/Neurokinin B\/Dynorphin (KNDy) Cells as Integrators of Diverse Internal and External Cues: Evidence From Viral-Based Monosynaptic Tract-Tracing in Mice","volume":"9","author":"Moore","year":"2019","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0213927","DOI":"10.1371\/journal.pone.0213927","article-title":"Mapping Neuronal Inputs to Kiss1 Neurons in the Arcuate Nucleus of the Mouse","volume":"14","author":"Yeo","year":"2019","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-1498","article-title":"Regulation of Kiss1 Expression by Sex Steroids in the Amygdala of the Rat and Mouse","volume":"152","author":"Kim","year":"2011","journal-title":"Endocrinology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0183596","DOI":"10.1371\/journal.pone.0183596","article-title":"Role of Amygdala Kisspeptin in Pubertal Timing in Female Rats","volume":"12","author":"Adekunbi","year":"2017","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e12823","DOI":"10.1111\/jne.12823","article-title":"Optogenetic Stimulation of Kisspeptin Neurones Within the Posterodorsal Medial Amygdala Increases Luteinising Hormone Pulse Frequency in Female Mice","volume":"32","author":"Lass","year":"2020","journal-title":"J Neuroendocrinol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00373.2014","article-title":"In Vivo Electrophysiological Recordings in Amygdala Subnuclei Reveal Selective and Distinct Responses to a Behaviorally Identified Predator Odor","volume":"113","author":"Govic","year":"2015","journal-title":"J Neurophysiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2009.01940.x","article-title":"Corticotrophin-Releasing Factor Alters the Timing of Puberty in the Female Rat","volume":"22","author":"Kinsey-Jones","year":"2010","journal-title":"J Neuroendocrinol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4346","article-title":"Ucn3 and CRF-R2 in the Medial Amygdala Regulate Complex Social Dynamics","volume":"19","author":"Shemesh","year":"2016","journal-title":"Nat Neurosci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0545","article-title":"Urocortin 3 Modulates the Neuroendocrine Stress Response and Is Regulated in Rat Amygdala and Hypothalamus by Stress and Glucocorticoids","volume":"147","author":"Jamieson","year":"2006","journal-title":"Endocrinology"},{"key":"B31","first-page":"246","article-title":"Mouse brain in stereotaxic coordinates","author":"Paxinos","year":"2019"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e59439","DOI":"10.3791\/59439","article-title":"Non-Invasive Strategies for Chronic Manipulation of Dreadd-Controlled Neuronal Activity","volume":"2019","author":"Zhan","year":"2019","journal-title":"J Vis Exp"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1502","article-title":"Development of a Methodology for and Assessment of Pulsatile Luteinizing Hormone Secretion in Juvenile and Adult Male Mice","volume":"154","author":"Steyn","year":"2013","journal-title":"Endocrinology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e39001","DOI":"10.1371\/journal.pone.0039001","article-title":"Dynpeak: An Algorithm for Pulse Detection and Frequency Analysis in Hormonal Time Series","volume":"7","author":"Vidal","year":"2012","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/0091-3057(95)02171-X","article-title":"The Influence of Open Arm Ledges and Maze Experience in the Elevated Plus-Maze","volume":"54","author":"Fernandes","year":"1996","journal-title":"Pharmacol Biochem Behav"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.1210\/EN.2012-1529","article-title":"Increased Neurokinin B (Tac2) Expression in the Mouse Arcuate Nucleus Is an Early Marker of Pubertal Onset With Differential Sensitivity to Sex Steroid-Negative Feedback Than Kiss1","volume":"153","author":"Gill","year":"2012","journal-title":"Endocrinology"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1210\/EN.2014-2012","article-title":"Substance P Regulates Puberty Onset and Fertility in the Female Mouse","volume":"156","author":"Simavli","year":"2015","journal-title":"Endocrinology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/S41598-021-81689-4","article-title":"Polycomb Represses a Gene Network Controlling Puberty via Modulation of Histone Demethylase Kdm6b Expression","volume":"11","author":"Wright","year":"2021","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e12572","DOI":"10.1111\/jne.12572","article-title":"Kisspeptin Neurones in the Posterodorsal Medial Amygdala Modulate Sexual Partner Preference and Anxiety in Male Mice","volume":"30","author":"Adekunbi","year":"2018","journal-title":"J Neuroendocrinol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"SUN","DOI":"10.1210\/jendso\/bvaa046.2143","article-title":"Chronic Exposure to Predator Odour Stress Disrupts LH Pulsatility and Delays Puberty While Activation of Amygdala Kisspeptin Advances Puberty","author":"Ivanova","year":"2020","journal-title":"Endocr Soc"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/J.PSYNEUEN.2021.105154","article-title":"Chronic Psychosocial Stress and Experimental Pubertal Delay Affect Socioemotional Behavior and Amygdala Functional Connectivity in Adolescent Female Rhesus Macaques","volume":"127","author":"Pincus","year":"2021","journal-title":"Psychoneuroendocrinology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00301","article-title":"Acute Psychosocial Stress Inhibits LH Pulsatility and Kiss1 Neuronal Activation in Female Mice","volume":"158","author":"Yang","year":"2017","journal-title":"Endocrinology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep46381","article-title":"Development and Validation of a Method for Precise Dating of Female Puberty in Laboratory Rodents: The Puberty Ovarian Maturation Score (Pub-Score)","volume":"7","author":"Gaytan","year":"2017","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jaac.2015.10.004","article-title":"Developmental Timing of Trauma Exposure Relative to Puberty and the Nature of Psychopathology Among Adolescent Girls","volume":"55","author":"Marshall","year":"2016","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41398-018-0092-z","article-title":"Amygdala Hyper-Connectivity in a Mouse Model of Unpredictable Early Life Stress","volume":"8","author":"Johnson","year":"2018","journal-title":"Transl Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-1003","article-title":"The Role of the Medial and Central Amygdala in Stress-Induced Suppression of Pulsatile LH Secretion in Female Rats","volume":"152","author":"Lin","year":"2011","journal-title":"Endocrinology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-09926-z","article-title":"Individual Variability in Behavior and Functional Networks Predicts Vulnerability Using an Animal Model of PTSD","volume":"10","author":"Dopfel","year":"2019","journal-title":"Nat Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2008.00763.x","article-title":"Age- and Sex-Dependent Effects of Footshock Stress on Subsequent Alcohol Drinking and Acoustic Startle Behavior in Mice Selectively Bred for High-Alcohol Preference","volume":"32","author":"Chester","year":"2008","journal-title":"Alcohol Clin Exp Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2008.01807.x","article-title":"Down-Regulation of Hypothalamic Kisspeptin and its Receptor, Kiss1r, mRNA Expression Is Associated With Stress-Induced Suppression of Luteinising Hormone Secretion in the Female Rat","volume":"21","author":"Kinsey-Jones","year":"2009","journal-title":"J Neuroendocrinol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"37","DOI":"10.53260\/grem.201017","article-title":"Serum Kisspeptin and Corticotropin-Releasing Hormone Levels in Patients With Functional Hypothalamic Amenorrhea","volume":"1","author":"Agnieszka","year":"2020","journal-title":"Gynecol Reprod Endocrinol Metab"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-0950","article-title":"Role of Corticotropin-Releasing Factor Receptor-2 in Stress-Induced Suppression of Pulsatile Luteinizing Hormone Secretion in the Rat","volume":"146","author":"Li","year":"2005","journal-title":"Endocrinology"},{"key":"B52","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.neuroscience.2009.03.078","article-title":"Social Defeat Stress Activates Medial Amygdala Cells That Express Type 2 Corticotropin-Releasing Factor Receptor mRNA","volume":"162","author":"Fekete","year":"2009","journal-title":"Neuroscience"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2012.00033","article-title":"Differential Efferent Projections of the Anterior, Posteroventral, and Posterodorsal Subdivisions of the Medial Amygdala in Mice","volume":"6","author":"Pardo-Bellver","year":"2012","journal-title":"Front Neuroanat"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1049-10.2010","article-title":"Urocortin 3 Modulates Social Discrimination Abilities via Corticotropin-Releasing Hormone Receptor Type 2","volume":"30","author":"Deussing","year":"2010","journal-title":"J Neurosci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.03.043","article-title":"Distribution of Urocortin 3 Neurons Innervating the Ventral Premammillary Nucleus in the Rat Brain","volume":"1089","author":"Cavalcante","year":"2006","journal-title":"Brain Res"},{"key":"B56","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1523\/jneurosci.22-03-00991.2002","article-title":"Urocortin III-Immunoreactive Projections in Rat Brain: Partial Overlap With Sites of Type 2 Corticotrophin-Releasing Factor Receptor Expression","volume":"22","author":"Li","year":"2002","journal-title":"J Neurosci"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep11208","article-title":"Puberty Timing Associated With Diabetes, Cardiovascular Disease and Also Diverse Health Outcomes in Men and Women: The UK Biobank Study","volume":"5","author":"Day","year":"2015","journal-title":"Sci Rep"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1101\/2022.01.27.477996","article-title":"Role of Posterodorsal Medial Amygdala Urocortin-3 in Pubertal Timing in Female Mice","author":"Ivanova","year":"2022","journal-title":"bioRxiv"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.893029\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T07:55:15Z","timestamp":1652774115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.893029\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,17]]},"references-count":58,"alternative-id":["10.3389\/fendo.2022.893029"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.893029","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,17]]},"article-number":"893029"}}