{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:18:50Z","timestamp":1790882330434,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Second Affiliated Hospital of Dalian Medical University","award":["2022LCJSGC13"],"award-info":[{"award-number":["2022LCJSGC13"]}]},{"name":"Second Affiliated Hospital of Dalian Medical University","award":["2022LCJSZD03"],"award-info":[{"award-number":["2022LCJSZD03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Hypothyroidism is closely related to mental disorders, mainly depression, through an as-yet-unknown mechanism. The cerebral inflammatory immune process has been implied to play a pivotal role in the onset of affective symptoms in several conditions. In order to gain insight into the mechanism underlying the depressive behaviors in hypothyroid rats, brain microglial activation was evaluated using micro positron emission tomography imaging with a translocator protein (TSPO) radioligand. Hypothyroidism was induced in adult male Wistar rats by administration of 0.05% propylthiouracil in drinking water for five weeks. Open field, forced swimming and tail suspension tests were employed to evaluate the depressive behavior in hypothyroid rats, and the relationship between the behavioral changes and brain microglial activation was evaluated using [18F] DPA-714 micro positron emission tomography imaging. The open field test revealed significantly reduced first-minute activity and rearing behavior in the hypothyroid group, as well as significantly increased immobility in the forced swimming test and the tail suspension test. Hypothyroidism induced significantly increased microglial activation in the hippocampus. The radioligand uptake in the hippocampus correlated negatively with first-minute activity in the open field test (p &lt; 0.05), and the radioligand uptake in the hippocampus correlated positively with changes in the immobility time in the forced swimming test and the tail suspension test (p &lt; 0.05). Immunohistochemistry also confirmed the activation of microglia and inflammatory bodies in hypothyroid rats. The results indicate that hypothyroidism can induce depressive behavior in adult Wistar rats, microglial activation in the hippocampus plays an important role in the depressive behavior in hypothyroid rats and the inflammatory immune mechanism may underlie the behavioral abnormalities in thyroid dysfunction. Furthermore, the findings in the present study suggest there might be a common mechanism underlying depressive behavior in adult-onset hypothyroidism and depression.<\/jats:p>","DOI":"10.3390\/ph16020279","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T02:16:01Z","timestamp":1676340961000},"page":"279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inflammatory Immune Process and Depression-like Behavior in Hypothyroid Rats: A [18F] DPA-714 Micro Positron Emission Tomography Study"],"prefix":"10.3390","volume":"16","author":[{"given":"Yizhen","family":"Wang","sequence":"first","affiliation":[{"name":"Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aijuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China"},{"name":"Nuclear Medicine Division, Shengli Oilfield Central Hospital, Dongying 257000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yu","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianer","family":"Ling","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China"},{"name":"Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo 315010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3389\/fendo.2016.00044","article-title":"Resveratrol Ameliorates the Anxiety- and Depression-like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt\/\u03b2-Catenin Pathway","volume":"7","author":"Ge","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/MED.0000000000000089","article-title":"Psychiatric and Cognitive Manifestations of Hypothyroidism","volume":"21","author":"Samuels","year":"2014","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/sj.mp.4000963","article-title":"Thyroid Hormones, Serotonin and Mood: Of Synergy and Significance in the Adult Brain","volume":"7","author":"Bauer","year":"2002","journal-title":"Mol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1055\/s-2003-45133","article-title":"Thyroid, Brain and Mood Modulation in Affective Disorder: Insights from Molecular Research and Functional Brain Imaging","volume":"36","author":"Bauer","year":"2003","journal-title":"Pharmacopsychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1212\/WNL.0000000000002485","article-title":"Neuroinflammation in Treated HIV-Positive Individuals: A TSPO PET Study","volume":"86","author":"Vera","year":"2016","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1210\/endo-125-2-1103","article-title":"Thyroid Hormones and the Acquisition and Retention of Behavioural Responses","volume":"125","author":"Jefferys","year":"1989","journal-title":"Endocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ijid.2019.05.010","article-title":"Cognitive Impairment in HTLV-1-Associated Myelopathy, Proviral Load and Inflammatory Markers","volume":"84","author":"Champs","year":"2019","journal-title":"Int. J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1007\/s00415-017-8565-1","article-title":"The Role of TSPO PET in Assessing Neuroinflammation","volume":"264","author":"Crawshaw","year":"2017","journal-title":"J. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00259-014-2939-8","article-title":"18F-GE-180: A Novel TSPO Radiotracer Compared to 11C-R-PK11195 in a Preclinical Model of Stroke","volume":"42","author":"Boutin","year":"2015","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00259-011-2041-4","article-title":"The Translocator Protein Ligand [18F]DPA-714 Images Glioma and Activated Microglia in Vivo","volume":"39","author":"Winkeler","year":"2012","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/jne.12283","article-title":"Thyroid Hormone and Astroglia: Endocrine Control of the Neural Environment","volume":"27","author":"Dezonne","year":"2015","journal-title":"J. Neuroendocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.steroids.2012.02.018","article-title":"Nongenomic Effects of Thyroid Hormones on the Immune System Cells: New Targets, Old Players","volume":"77","author":"Balducci","year":"2012","journal-title":"Steroids"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1089\/thy.2010.0429","article-title":"Thyroid Hormones as Modulators of Immune Activities at the Cellular Level","volume":"21","author":"Incerpi","year":"2011","journal-title":"Thyroid"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1677\/joe.1.06137","article-title":"Integrative Study of Hypothalamus-Pituitary-Thyroid-Immune System Interaction: Thyroid Hormone-Mediated Modulation of Lymphocyte Activity through the Protein Kinase C Signaling Pathway","volume":"189","author":"Klecha","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1523\/JNEUROSCI.21-06-02028.2001","article-title":"Regulation of Microglial Development: A Novel Role for Thyroid Hormone","volume":"21","author":"Lima","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12974-018-1054-3","article-title":"Microglial Activation Mediates Chronic Mild Stress-Induced Depressive- and Anxiety-like Behavior in Adult Rats","volume":"15","author":"Wang","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41398-020-01155-z","article-title":"PET Evaluation of Light-Induced Modulation of Microglial Activation and GLP-1R Expression in Depressive Rats","volume":"11","author":"Liu","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbr.2004.11.012","article-title":"Attention-Deficit and Hyperactive Neurobehavioural Characteristics Induced by Perinatal Hypothyroidism in Rats","volume":"159","author":"Negishi","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/0892-0362(91)90077-A","article-title":"Hyperactivity and Spatial Maze Learning Impairment of Adult Rats with Temporary Neonatal Hypothyroidism","volume":"13","author":"Akaike","year":"1991","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1055\/s-0037-1608715","article-title":"TSPO-PET Imaging to Assess Cerebral Microglial Activation in Multiple Sclerosis","volume":"37","author":"Singhal","year":"2017","journal-title":"Semin. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/0031-9384(87)90140-5","article-title":"Altered Responsiveness to Ambiental Stimuli in Altered Thyroidal States","volume":"41","author":"Rial","year":"1987","journal-title":"Physiol. Behav."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.bbr.2014.06.019","article-title":"A Behavioral and Micro Positron Emission Tomography Imaging Study in a Rat Model of Hypothyroidism","volume":"271","author":"Yu","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0014-2999(78)90414-4","article-title":"\u201cBehavioural Despair\u201d in Rats and Mice: Strain Differences and the Effects of Imipramine","volume":"51","author":"Porsolt","year":"1978","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0304-3940(97)00664-2","article-title":"Experimental Hypothyroidism Increases Immobility in Rats in the Forced Swim Paradigm","volume":"234","author":"Kulikov","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1007\/s12020-013-0001-4","article-title":"Depression-like Behavior in Subclinical Hypothyroidism Rat Induced by Hemi-Thyroid Electrocauterization","volume":"45","author":"Ge","year":"2014","journal-title":"Endocrine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/sj.npp.1380101","article-title":"Synaptosomal T3 Content in Cerebral Cortex of Adult Rat in Different Thyroidal States","volume":"11","author":"Sarkar","year":"1994","journal-title":"Neuropsychopharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/j.1365-2826.2010.02002.x","article-title":"Adult-Onset Hypothyroidism Induces the Amyloidogenic Pathway of Amyloid Precursor Protein Processing in the Rat Hippocampus","volume":"22","author":"Ghenimi","year":"2010","journal-title":"J. Neuroendocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ejphar.2018.01.017","article-title":"Chrysin Reverses the Depressive-like Behavior Induced by Hypothyroidism in Female Mice by Regulating Hippocampal Serotonin and Dopamine","volume":"822","author":"Bortolotto","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yu, J., Tian, A.J., Yuan, X., and Cheng, X.X. (2016). Subclinical Hypothyroidism after 131I-Treatment of Graves\u2019 Disease: A Risk Factor for Depression?. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154846"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3682","DOI":"10.1210\/en.2016-1272","article-title":"Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice","volume":"157","author":"Bocco","year":"2016","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1038\/jcbfm.2010.63","article-title":"Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation","volume":"30","author":"Owen","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/jcbfm.2011.147","article-title":"An 18-KDa Translocator Protein (TSPO) Polymorphism Explains Differences in Binding Affinity of the PET Radioligand PBR28","volume":"32","author":"Owen","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104186","DOI":"10.1016\/j.beproc.2020.104186","article-title":"The Diurnal Variation of Open-Field Habituation in Rats","volume":"178","author":"Poveda","year":"2020","journal-title":"Behav. Process."},{"key":"ref_34","first-page":"e52587","article-title":"The Forced Swim Test as a Model of Depressive-like Behavior","volume":"2015","author":"Franko","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.biopha.2018.07.040","article-title":"Gypenosides Reverses Depressive Behavior via Inhibiting Hippocampal Neuroinflammation","volume":"106","author":"Dong","year":"2018","journal-title":"Biomed. Pharmacother."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/2\/279\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:33:46Z","timestamp":1760121226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/2\/279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,13]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ph16020279"],"URL":"https:\/\/doi.org\/10.3390\/ph16020279","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,13]]}}}