{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T19:10:16Z","timestamp":1754161816847,"version":"3.41.2"},"reference-count":58,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005117","name":"Birjand University of Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005117","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder that disrupts fetal central nervous system (CNS) development. This study investigates the effects of maternal diabetes on hippocampal structure and autophagy\u2010related mechanisms in neonatal rats, focusing on the PI3K\/mTOR signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Forty female Wistar rats were divided into three groups: control (CON), diabetic (STZ\u2010D), and insulin\u2010treated diabetic (STZ\u2010INS). Hyperglycemia was induced using streptozotocin, and offspring were analyzed at postnatal day 14 (P14). Histological evaluations of hippocampal structure were conducted using hematoxylin and eosin (H&amp;E) staining, and neuronal damage was assessed with toluidine blue staining. Autophagy\u2010related gene expression (Beclin\u20101, LC\u20103, ATG\u20107) and the PI3K\/mTOR signaling pathway were examined using real\u2010time PCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Offspring from the STZ\u2010D group exhibited significant reductions in hippocampal volume and increased dark neurons in the CA1 and CA2 regions compared to the CON and STZ\u2010INS groups. Gene expression analysis revealed a marked downregulation of ATG\u20107 and significant upregulation of PI3K and mTOR in the STZ\u2010D group, while Beclin\u20101 and LC\u20103 showed no significant changes. Insulin treatment mitigated these adverse effects, preserving hippocampal structure and reducing neuronal damage. In addition, the results of the Voronoi tessellation method showed that hippocampal neural cells depict a regular pattern in different subfields in all experimental groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Maternal hyperglycemia disrupts hippocampal development by altering autophagy and activating the PI3K\/mTOR pathway, contributing to neuronal damage. Insulin treatment during pregnancy can counteract these effects, emphasizing the importance of glycemic control. These findings highlight potential therapeutic targets for mitigating CNS impairments in the offspring of diabetic mothers.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70518","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T06:44:34Z","timestamp":1752561874000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurodevelopmental Consequences of Maternal Diabetes: Autophagy and Spatial Arrangement of Hippocampal Neurons"],"prefix":"10.1111","volume":"31","author":[{"given":"Saleheh Mansouri","family":"Boutegaz","sequence":"first","affiliation":[{"name":"Department of Anatomical Sciences, Faculty of Medicine Birjand University of Medical Sciences  Birjand Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6635-2717","authenticated-orcid":false,"given":"Mohammad Reza","family":"Namavar","sequence":"additional","affiliation":[{"name":"Histomorphometry and Stereology Research Center Shiraz University of Medical Sciences  Shiraz Iran"},{"name":"Clinical Neurology Research Center Shiraz University of Medical Sciences  Shiraz Iran"},{"name":"Department of Anatomical Sciences, School of Medicine Shiraz University of Medical Sciences  Shiraz Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4368-2139","authenticated-orcid":false,"given":"Mehri","family":"Shadi","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences, Faculty of Medicine Birjand University of Medical Sciences  Birjand Iran"},{"name":"Cellular &amp; Molecular Research Center Birjand University of Medical Sciences  Birjand Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamid","family":"Kabiri\u2010rad","sequence":"additional","affiliation":[{"name":"Cellular &amp; Molecular Research Center Birjand University of Medical Sciences  Birjand Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0970-9334","authenticated-orcid":false,"given":"Saeed","family":"Vafaei\u2010Nezhad","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences, Faculty of Medicine Birjand University of Medical Sciences  Birjand Iran"},{"name":"Cellular &amp; Molecular Research Center Birjand University of Medical Sciences  Birjand Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_11_2_1","DOI":"10.3390\/jcm11195736"},{"doi-asserted-by":"publisher","key":"e_1_2_11_3_1","DOI":"10.1210\/endrev\/bnac003"},{"doi-asserted-by":"publisher","key":"e_1_2_11_4_1","DOI":"10.1016\/j.diabres.2021.109050"},{"doi-asserted-by":"publisher","key":"e_1_2_11_5_1","DOI":"10.1016\/j.biopha.2021.112183"},{"doi-asserted-by":"publisher","key":"e_1_2_11_6_1","DOI":"10.3390\/ijms22062965"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2021-067946","article-title":"Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes: Systematic Review and Meta\u2010Analysis","volume":"377","author":"Ye W.","year":"2022","journal-title":"BMJ"},{"doi-asserted-by":"publisher","key":"e_1_2_11_8_1","DOI":"10.2337\/dc20-0261"},{"issue":"7","key":"e_1_2_11_9_1","article-title":"Cognitive Function in Offspring of Mothers With Gestational Diabetes\u2013the Role of Insulin Receptor","volume":"2","author":"Hami J.","year":"2016","journal-title":"MOJ Anatomy & Physiology"},{"doi-asserted-by":"publisher","key":"e_1_2_11_10_1","DOI":"10.4239\/wjd.v6.i3.412"},{"doi-asserted-by":"publisher","key":"e_1_2_11_11_1","DOI":"10.4103\/jpn.JPN_144_16"},{"volume-title":"Hippocampus\u2010Cytoarchitecture and Diseases","year":"2021","author":"Vafaei\u2010Nezhad S.","key":"e_1_2_11_12_1"},{"doi-asserted-by":"publisher","key":"e_1_2_11_13_1","DOI":"10.1016\/j.neuroscience.2016.01.025"},{"volume-title":"The Hippocampus Book","year":"2024","author":"Morris R.","key":"e_1_2_11_14_1"},{"doi-asserted-by":"publisher","key":"e_1_2_11_15_1","DOI":"10.1007\/s11011-016-9864-4"},{"doi-asserted-by":"publisher","key":"e_1_2_11_16_1","DOI":"10.1016\/j.neulet.2018.05.033"},{"doi-asserted-by":"publisher","key":"e_1_2_11_17_1","DOI":"10.3390\/cells11152262"},{"doi-asserted-by":"publisher","key":"e_1_2_11_18_1","DOI":"10.1016\/j.tins.2020.07.003"},{"doi-asserted-by":"publisher","key":"e_1_2_11_19_1","DOI":"10.1016\/j.jmb.2020.01.017"},{"doi-asserted-by":"publisher","key":"e_1_2_11_20_1","DOI":"10.1016\/j.mam.2021.100972"},{"doi-asserted-by":"publisher","key":"e_1_2_11_21_1","DOI":"10.1016\/j.neulet.2018.04.017"},{"doi-asserted-by":"publisher","key":"e_1_2_11_22_1","DOI":"10.1080\/15548627.2021.1943177"},{"doi-asserted-by":"publisher","key":"e_1_2_11_23_1","DOI":"10.1016\/j.jchemneu.2021.102010"},{"doi-asserted-by":"publisher","key":"e_1_2_11_24_1","DOI":"10.1016\/j.jchemneu.2021.101924"},{"doi-asserted-by":"publisher","key":"e_1_2_11_25_1","DOI":"10.1007\/s11011-017-9950-2"},{"doi-asserted-by":"publisher","key":"e_1_2_11_26_1","DOI":"10.1016\/j.jstrokecerebrovasdis.2021.105630"},{"volume-title":"The Rat Brain in Stereotaxic Coordinates: Hard Cover Edition","year":"2006","author":"Paxinos G.","key":"e_1_2_11_27_1"},{"doi-asserted-by":"publisher","key":"e_1_2_11_28_1","DOI":"10.1530\/JOE-21-0332"},{"doi-asserted-by":"publisher","key":"e_1_2_11_29_1","DOI":"10.1007\/s13410-018-0618-1"},{"doi-asserted-by":"publisher","key":"e_1_2_11_30_1","DOI":"10.1007\/s11011-016-9802-5"},{"volume-title":"The Impacts of Maternal Diabetes in Pregnancy on Cerebellum Development in Offspring","year":"2018","author":"Hami J.","key":"e_1_2_11_31_1"},{"doi-asserted-by":"publisher","key":"e_1_2_11_32_1","DOI":"10.1016\/j.jchemneu.2019.101669"},{"doi-asserted-by":"publisher","key":"e_1_2_11_33_1","DOI":"10.1007\/s12035-022-02951-y"},{"doi-asserted-by":"publisher","key":"e_1_2_11_34_1","DOI":"10.34172\/ahj.1481"},{"doi-asserted-by":"publisher","key":"e_1_2_11_35_1","DOI":"10.34172\/jlms.2022.32"},{"doi-asserted-by":"publisher","key":"e_1_2_11_36_1","DOI":"10.34172\/jlms.2022.36"},{"doi-asserted-by":"publisher","key":"e_1_2_11_37_1","DOI":"10.34172\/jlms.2020.59"},{"doi-asserted-by":"publisher","key":"e_1_2_11_38_1","DOI":"10.1007\/s00580-024-03607-0"},{"doi-asserted-by":"publisher","key":"e_1_2_11_39_1","DOI":"10.1016\/j.ijdevneu.2016.04.009"},{"doi-asserted-by":"publisher","key":"e_1_2_11_40_1","DOI":"10.1097\/MCO.0b013e3281e38774"},{"key":"e_1_2_11_41_1","first-page":"156","article-title":"Anti\u2010Inflammatory Effect of Insulin and Its Mechanism: An Exploratory Study","volume":"12","author":"Dong Q.","year":"2018","journal-title":"Chinese Journal of Diabetes"},{"doi-asserted-by":"publisher","key":"e_1_2_11_42_1","DOI":"10.2337\/db14-0568"},{"doi-asserted-by":"publisher","key":"e_1_2_11_43_1","DOI":"10.1155\/2012\/384017"},{"doi-asserted-by":"publisher","key":"e_1_2_11_44_1","DOI":"10.1016\/S1474-4422(04)00681-7"},{"doi-asserted-by":"publisher","key":"e_1_2_11_45_1","DOI":"10.1053\/j.semtcvs.2006.06.003"},{"doi-asserted-by":"publisher","key":"e_1_2_11_46_1","DOI":"10.1002\/cne.24880"},{"doi-asserted-by":"publisher","key":"e_1_2_11_47_1","DOI":"10.1016\/j.jchemneu.2021.102000"},{"doi-asserted-by":"publisher","key":"e_1_2_11_48_1","DOI":"10.1016\/j.jchemneu.2019.04.007"},{"doi-asserted-by":"publisher","key":"e_1_2_11_49_1","DOI":"10.1016\/j.nbd.2021.105582"},{"doi-asserted-by":"publisher","key":"e_1_2_11_50_1","DOI":"10.1038\/s41418-020-0497-0"},{"doi-asserted-by":"publisher","key":"e_1_2_11_51_1","DOI":"10.1038\/nature04723"},{"doi-asserted-by":"publisher","key":"e_1_2_11_52_1","DOI":"10.1016\/j.cmet.2011.06.008"},{"doi-asserted-by":"publisher","key":"e_1_2_11_53_1","DOI":"10.1038\/cdd.2014.229"},{"doi-asserted-by":"publisher","key":"e_1_2_11_54_1","DOI":"10.1002\/path.5576"},{"doi-asserted-by":"publisher","key":"e_1_2_11_55_1","DOI":"10.3389\/fcell.2020.00138"},{"doi-asserted-by":"publisher","key":"e_1_2_11_56_1","DOI":"10.3389\/fnins.2019.00491"},{"doi-asserted-by":"publisher","key":"e_1_2_11_57_1","DOI":"10.3389\/fncel.2019.00196"},{"issue":"3","key":"e_1_2_11_58_1","first-page":"216","article-title":"Autophagy Inhibitor 3\u2010Methyladenine Regulates the Expression of LC3, Beclin\u20101 and ZnTs in Rat Cerebral Cortex Following Recurrent Neonatal Seizures","volume":"1","author":"Ni H.","year":"2010","journal-title":"World Journal of Emergency Medicine"},{"doi-asserted-by":"publisher","key":"e_1_2_11_59_1","DOI":"10.3389\/fmed.2021.644121"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70518","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T10:13:10Z","timestamp":1753783990000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":58,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1111\/cns.70518"],"URL":"https:\/\/doi.org\/10.1111\/cns.70518","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"type":"print","value":"1755-5930"},{"type":"electronic","value":"1755-5949"}],"subject":[],"published":{"date-parts":[[2025,7]]},"assertion":[{"value":"2025-03-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70518"}}