{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:57:24Z","timestamp":1792015044763,"version":"4.4.0"},"reference-count":109,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["E-26\/210.190\/2018, E-26\/202.572\/2019"],"award-info":[{"award-number":["E-26\/210.190\/2018, E-26\/202.572\/2019"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"crossref","award":["BPP-304474\/2015-0, BPP 306037\/2019-0"],"award-info":[{"award-number":["BPP-304474\/2015-0, BPP 306037\/2019-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Grant PAEF2-IOC\/Fiocruz"},{"DOI":"10.13039\/501100002322","name":"CAPES","doi-asserted-by":"crossref","award":["Code 001"],"award-info":[{"award-number":["Code 001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The Apicomplexa protozoan<jats:italic>Toxoplasma gondii<\/jats:italic>is a mandatory intracellular parasite and the causative agent of toxoplasmosis. This illness is of medical importance due to its high prevalence worldwide and may cause neurological alterations in immunocompromised persons. In chronically infected immunocompetent individuals, this parasite forms tissue cysts mainly in the brain. In addition,<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>infection has been related to mental illnesses such as schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder, as well as mood, personality, and other behavioral changes. In the present study, we evaluated the kinetics of behavioral alterations in a model of chronic infection, assessing anxiety, depression and exploratory behavior, and their relationship with neuroinflammation and parasite cysts in brain tissue areas, blood-brain-barrier (BBB) integrity, and cytokine status in the brain and serum. Adult female C57BL\/6 mice were infected by gavage with 5 cysts of the ME-49 type II<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>strain, and analyzed as independent groups at 30, 60 and 90 days postinfection (dpi). Anxiety, depressive-like behavior, and hyperactivity were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>infection, in a direct association with the presence of parasite cysts and neuroinflammation, independently of the brain tissue areas, and linked to BBB disruption. These behavioral alterations paralleled the upregulation of expression of tumor necrosis factor (TNF) and CC-chemokines (CCL2\/MCP-1, CCL3\/MIP-1\u03b1, CCL4\/MIP-1\u03b2 and CCL5\/RANTES) in the brain tissue. In addition, increased levels of interferon-gamma (IFN\u03b3), TNF and CCL2\/MCP-1 were detected in the peripheral blood, at 30 and 60 dpi. Our data suggest that the persistence of parasite cysts induces sustained neuroinflammation, and BBB disruption, thus allowing leakage of cytokines of circulating plasma into the brain tissue. Therefore, all these factors may contribute to behavioral changes (anxiety, depressive-like behavior, and hyperactivity) in chronic<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>infection.<\/jats:p>","DOI":"10.1371\/journal.pone.0258199","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T02:57:00Z","timestamp":1633489020000},"page":"e0258199","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":55,"title":["Behavioral alterations in long-term Toxoplasma gondii infection of C57BL\/6 mice are associated with neuroinflammation and disruption of the blood brain barrier"],"prefix":"10.1371","volume":"16","author":[{"given":"Leda","family":"Casta\u00f1o Barrios","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula","family":"Da Silva Pinheiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gibaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-6128","authenticated-orcid":true,"given":"Andrea Alice","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Machado Rodrigues e Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Roff\u00ea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helton","family":"da Costa Santiago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Tostes Gazzinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Roberto","family":"Mineo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neide Maria","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5503-6754","authenticated-orcid":true,"given":"Joseli","family":"Lannes-Vieira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"pone.0258199.ref001","article-title":"Sur un protozoaire nouveau du gondii","author":"C Nicole","year":"1909","journal-title":"Acad Sci"},{"key":"pone.0258199.ref002","first-page":"109","article-title":"Un nuovo protozoa parassita de\u2019conigli. incontrato nelle lesioni anatomiche d\u2019une malattia che ricorda in molti punti il Kala-azar dell\u2019uomo. Nota preliminare pel","volume":"3","author":"A Splendore","year":"1908","journal-title":"Rev Soc Sci Sao Paulo"},{"issue":"12","key":"pone.0258199.ref003","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.ijpara.2009.04.003","article-title":"Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis","volume":"39","author":"G Pappas","year":"2009","journal-title":"Int J Parasitol"},{"key":"pone.0258199.ref004","first-page":"117","article-title":"Epidemiologia da Toxoplasmose. Souza W, and Belfort JR Toxoplasmose & Toxoplasma gondii","author":"JL Jones","year":"2014","journal-title":"Rio de Janeiro Editora Fiocruz"},{"issue":"4","key":"pone.0258199.ref005","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/aje\/154.4.357","article-title":"Toxoplasma gondii Infection in the United States: Seroprevalence and Risk Factors","volume":"154","author":"JL Jones","year":"2001","journal-title":"American Journal of Epidemiology"},{"issue":"2","key":"pone.0258199.ref006","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1128\/CMR.11.2.267","article-title":"Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts","volume":"11","author":"JP Dubey","year":"1998","journal-title":"Clinical microbiology reviews"},{"key":"pone.0258199.ref007","first-page":"33","volume-title":"Toxoplasmose & Toxoplasma gondii:","author":"HS Barbosa","year":"2014"},{"key":"pone.0258199.ref008","doi-asserted-by":"crossref","first-page":"e00036","DOI":"10.1016\/j.fawpar.2019.e00036","article-title":"Treatment of toxoplasmosis: Current options and future perspectives","volume":"15","author":"N Konstantinovic","year":"2019","journal-title":"Food and waterborne parasitology"},{"key":"pone.0258199.ref009","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1742-2094-5-48","article-title":"Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection","volume":"5","author":"G Hermes","year":"2008","journal-title":"Journal of neuroinflammation"},{"issue":"2","key":"pone.0258199.ref010","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.celrep.2019.12.019","article-title":"Neuroinflammation-Associated Aspecific Manipulation of Mouse Predator Fear by Toxoplasma gondii","volume":"30","author":"M Boillat","year":"2020","journal-title":"Cell Rep"},{"issue":"1","key":"pone.0258199.ref011","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13195-017-0241-2","article-title":"Role of neuroinflammation in neurodegeneration: new insights","volume":"9","author":"RM McManus","year":"2017","journal-title":"Alzheimer\u2019s Research & Therapy"},{"issue":"3","key":"pone.0258199.ref012","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1093\/schbul\/sbl074","article-title":"Effects of Toxoplasma on human behavior","volume":"33","author":"J Flegr","year":"2007","journal-title":"Schizophrenia bulletin"},{"key":"pone.0258199.ref013","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1471-2334-2-11","article-title":"Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study","volume":"2","author":"J Flegr","year":"2002","journal-title":"BMC Infect Dis"},{"issue":"12","key":"pone.0258199.ref014","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1097\/NMD.0b013e3181c29a23","article-title":"Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders","volume":"197","author":"TA Arling","year":"2009","journal-title":"J Nerv Ment Dis"},{"issue":"6","key":"pone.0258199.ref015","doi-asserted-by":"crossref","DOI":"10.3390\/nu9060564","article-title":"Toxoplasma Gondii Moderates the Association between Multiple Folate-Cycle Factors and Cognitive Function in U.S. Adults","volume":"9","author":"AN Berrett","year":"2017","journal-title":"Nutrients"},{"issue":"1","key":"pone.0258199.ref016","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3181\/00379727-41-10577","article-title":"Biological and Immunological Identity of Toxoplasma of Animal and Human Origin","volume":"41","author":"AB Sabin","year":"1939","journal-title":"Proceedings of the Society for Experimental Biology and Medicine"},{"issue":"15","key":"pone.0258199.ref017","doi-asserted-by":"crossref","first-page":"6442","DOI":"10.1073\/pnas.0608310104","article-title":"Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors","volume":"104","author":"A Vyas","year":"2007","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"9","key":"pone.0258199.ref018","doi-asserted-by":"crossref","first-page":"e75246","DOI":"10.1371\/journal.pone.0075246","article-title":"Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance","volume":"8","author":"WM Ingram","year":"2013","journal-title":"PLoS One"},{"key":"pone.0258199.ref019","first-page":"115","article-title":"Toxoplasma gondii infection damages the perineuronal nets in a murine model","author":"YdSR Meurer","year":"2020","journal-title":"Mem\u00f3rias do Instituto Oswaldo Cruz"},{"issue":"3","key":"pone.0258199.ref020","doi-asserted-by":"crossref","first-page":"e32489","DOI":"10.1371\/journal.pone.0032489","article-title":"Chronic Toxoplasma infection modifies the structure and the risk of host behavior","volume":"7","author":"C Afonso","year":"2012","journal-title":"PLoS One"},{"issue":"10","key":"pone.0258199.ref021","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1128\/IAI.00217-16","article-title":"Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala","volume":"84","author":"F Ihara","year":"2016","journal-title":"Infection and immunity"},{"issue":"2","key":"pone.0258199.ref022","doi-asserted-by":"crossref","first-page":"e00381","DOI":"10.1128\/mBio.00381-19","article-title":"Guanabenz Reverses a Key Behavioral Change Caused by Latent Toxoplasmosis in Mice by Reducing Neuroinflammation","volume":"10","author":"J Martynowicz","year":"2019","journal-title":"mBio"},{"issue":"7434","key":"pone.0258199.ref023","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature11729","article-title":"NLRP3 is activated in Alzheimer\u2019s disease and contributes to pathology in APP\/PS1 mice","volume":"493","author":"MT Heneka","year":"2013","journal-title":"Nature"},{"issue":"7","key":"pone.0258199.ref024","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.bbi.2012.07.009","article-title":"Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions","volume":"26","author":"G Vilar-Pereira","year":"2012","journal-title":"Brain, Behavior, and Immunity"},{"issue":"1","key":"pone.0258199.ref025","doi-asserted-by":"crossref","first-page":"e0244710","DOI":"10.1371\/journal.pone.0244710","article-title":"Memory impairment in chronic experimental Chagas disease: Benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue","volume":"16","author":"G Vilar-Pereira","year":"2021","journal-title":"PloS one"},{"issue":"4","key":"pone.0258199.ref026","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/sj.mp.4000872","article-title":"Treatment with interferon-alpha (IFN\u03b1) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN\u03b1-induced depressive and anxiety symptoms and immune activation","volume":"6","author":"M Maes","year":"2001","journal-title":"Molecular Psychiatry"},{"issue":"5","key":"pone.0258199.ref027","doi-asserted-by":"crossref","first-page":"806","DOI":"10.2307\/3281034","article-title":"Antigenic differences between endozoites and cystozoites of Toxoplasma gondii","volume":"69","author":"MN Lunde","year":"1983","journal-title":"J Parasitol"},{"issue":"6","key":"pone.0258199.ref028","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1111\/j.1472-8206.2007.00526.x","article-title":"Animal models of anxiety in mice","volume":"21","author":"M Bourin","year":"2007","journal-title":"Fundam Clin Pharmacol"},{"key":"pone.0258199.ref029","volume-title":"The rat: a study in behavior","author":"SA Barnett","year":"1975"},{"issue":"3","key":"pone.0258199.ref030","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0014-2999(69)90197-6","article-title":"A new method for quantitative grip strength evaluation","volume":"6","author":"H van Riezen","year":"1969","journal-title":"Eur J Pharmacol"},{"issue":"3","key":"pone.0258199.ref031","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/BF00428203","article-title":"The tail suspension test: A new method for screening antidepressants in mice","volume":"85","author":"L Steru","year":"1985","journal-title":"Psychopharmacology"},{"issue":"1","key":"pone.0258199.ref032","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s002130100687","article-title":"Limitations on the use of the C57BL\/6 mouse in the tail suspension test","volume":"155","author":"AJ Mayorga","year":"2001","journal-title":"Psychopharmacology (Berl)"},{"issue":"2","key":"pone.0258199.ref033","first-page":"327","article-title":"Behavioral despair in mice: a primary screening test for antidepressants","volume":"229","author":"RD Porsolt","year":"1977","journal-title":"Arch Int Pharmacodyn Ther"},{"issue":"8","key":"pone.0258199.ref034","first-page":"3248","volume":"19","author":"RJ Carter","year":"1999","journal-title":"Characterization of progressive motor deficits in mice transgenic for the human Huntington\u2019s disease mutation"},{"key":"pone.0258199.ref035","first-page":"10.3791\/59878","article-title":"Low-Cost Gait Analysis for Behavioral Phenotyping of Mouse Models of Neuromuscular Disease","volume":"149","author":"V Wertman","year":"2019","journal-title":"J Vis Exp"},{"issue":"6","key":"pone.0258199.ref036","doi-asserted-by":"crossref","first-page":"ENEURO.0100-19.2019","DOI":"10.1523\/ENEURO.0100-19.2019","article-title":"Silhouette-Length-Scaled Gait Parameters for Motor Functional Analysis in Mice and Rats","volume":"6","author":"IK Timotius","year":"2019","journal-title":"eNeuro"},{"issue":"2","key":"pone.0258199.ref037","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.exppara.2010.04.019","article-title":"Toxoplasma gondii: the severity of toxoplasmic encephalitis in C57BL\/6 mice is associated with increased ALCAM and VCAM-1 expression in the central nervous system and higher blood-brain barrier permeability","volume":"126","author":"NM Silva","year":"2010","journal-title":"Exp Parasitol"},{"issue":"10","key":"pone.0258199.ref038","doi-asserted-by":"crossref","first-page":"e1002982","DOI":"10.1371\/journal.ppat.1002982","article-title":"Neuroimmunological blood brain barrier opening in experimental cerebral malaria","volume":"8","author":"A Nacer","year":"2012","journal-title":"PLoS Pathog"},{"key":"pone.0258199.ref039","volume-title":"The rat brain in stereotaxic coordinates: hard cover edition","author":"G Paxinos","year":"2006","edition":"4"},{"key":"pone.0258199.ref040","author":"A Talvani","year":"2000","journal-title":"Kinetics of cytokine gene expression in experimental chagasic cardiomyopathy: tissue parasitism and endogenous IFN-\u00ce as important determinants of chemokine mRNA expression during infection with Trypanosoma cruzi"},{"key":"pone.0258199.ref041","unstructured":"Allen Mouse Brain Atlas [Internet]. 2004 [cited May-8-2021]. Available from: http:\/\/atlas.brain-map.org\/atlas?atlas=2#atlas=2&plate=100884129&structure=549&x=7811.977914663461&y=4023.7296031071587&zoom=-3&resolution=16.11&z=5."},{"issue":"1","key":"pone.0258199.ref042","doi-asserted-by":"crossref","first-page":"12671","DOI":"10.1038\/srep12671","article-title":"Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria","volume":"5","author":"C Dende","year":"2015","journal-title":"Scientific Reports"},{"issue":"10","key":"pone.0258199.ref043","doi-asserted-by":"crossref","first-page":"e0204895","DOI":"10.1371\/journal.pone.0204895","article-title":"Toxoplasma gondii infection triggers chronic cachexia and sustained commensal dysbiosis in mice","volume":"13","author":"JA Hatter","year":"2018","journal-title":"PloS one"},{"key":"pone.0258199.ref044","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.bbr.2019.02.018","article-title":"Latent toxoplasmosis aggravates anxiety- and depressive-like behaviour and suggest a role of gene-environment interactions in the behavioural response to the parasite","volume":"364","author":"C Bay-Richter","year":"2019","journal-title":"Behavioural Brain Research"},{"issue":"1","key":"pone.0258199.ref045","doi-asserted-by":"crossref","first-page":"352","DOI":"10.4049\/jimmunol.1600914","article-title":"Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection","volume":"198","author":"RM Jin","year":"2017","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"issue":"7","key":"pone.0258199.ref046","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.micinf.2010.03.009","article-title":"Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology","volume":"12","author":"M Gulinello","year":"2010","journal-title":"Microbes and infection"},{"key":"pone.0258199.ref047","first-page":"774885","article-title":"The trajectory of gait development in mice","author":"S Akula","year":"2019","journal-title":"bioRxiv"},{"issue":"11","key":"pone.0258199.ref048","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1016\/j.joca.2016.03.008","article-title":"Gait analysis methods for rodent models of arthritic disorders: reviews and recommendations","volume":"24","author":"EH Lakes","year":"2016","journal-title":"Osteoarthritis and Cartilage"},{"issue":"2","key":"pone.0258199.ref049","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0165-0270(01)00485-X","article-title":"A simple method to measure stride length as an index of nigrostriatal dysfunction in mice","volume":"113","author":"PO Fernagut","year":"2002","journal-title":"J Neurosci Methods"},{"issue":"10","key":"pone.0258199.ref050","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1007\/s11916-014-0456-x","article-title":"Gait analysis methods for rodent models of osteoarthritis","volume":"18","author":"BY Jacobs","year":"2014","journal-title":"Current pain and headache reports"},{"key":"pone.0258199.ref051","doi-asserted-by":"crossref","first-page":"e3008","DOI":"10.7717\/peerj.3008","article-title":"Gait changes in a line of mice artificially selected for longer limbs","volume":"5","author":"LM Sparrow","year":"2017","journal-title":"PeerJ"},{"issue":"2","key":"pone.0258199.ref052","doi-asserted-by":"crossref","first-page":"026113","DOI":"10.1063\/1.3147408","article-title":"Gait dynamics in Parkinson\u2019s disease: common and distinct behavior among stride length, gait variability, and fractal-like scaling","volume":"19","author":"JM Hausdorff","year":"2009","journal-title":"Chaos (Woodbury, NY)"},{"issue":"10","key":"pone.0258199.ref053","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1212\/WNL.35.10.1450","article-title":"The gait abnormality of Huntington\u2019s disease","volume":"35","author":"WC Koller","year":"1985","journal-title":"Neurology"},{"issue":"1","key":"pone.0258199.ref054","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pain.2009.06.006","article-title":"Gait abnormalities differentially indicate pain or structural joint damage in monoarticular antigen-induced arthritis","volume":"145","author":"MK Boettger","year":"2009","journal-title":"PAIN\u00ae"},{"issue":"1","key":"pone.0258199.ref055","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1136\/annrheumdis-2013-203670","article-title":"AMPA\/kainate glutamate receptors contribute to inflammation, degeneration and pain related behaviour in inflammatory stages of arthritis","volume":"74","author":"CS Bonnet","year":"2013","journal-title":"Annals of the Rheumatic Diseases"},{"key":"pone.0258199.ref056","doi-asserted-by":"crossref","first-page":"595141","DOI":"10.5402\/2012\/595141","article-title":"Comparative evaluation of forced swim test and tail suspension test as models of negative symptom of schizophrenia in rodents","volume":"2012","author":"M Chatterjee","year":"2012","journal-title":"ISRN Psychiatry"},{"issue":"1","key":"pone.0258199.ref057","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13041-016-0196-4","article-title":"Comprehensive behavioral phenotyping of a new Semaphorin 3 F mutant mouse","volume":"9","author":"I Matsuda","year":"2016","journal-title":"Molecular Brain"},{"issue":"7","key":"pone.0258199.ref058","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1038\/sj.npp.1301537","article-title":"Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B)","volume":"33","author":"HT Zhang","year":"2008","journal-title":"Neuropsychopharmacology"},{"issue":"2","key":"pone.0258199.ref059","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4196\/kjpp.2009.13.2.79","article-title":"Maternal social separation of adolescent rats induces hyperactivity and anxiolytic behavior","volume":"13","author":"HR Kwak","year":"2009","journal-title":"The Korean journal of physiology & pharmacology: official journal of the Korean Physiological Society and the Korean Society of Pharmacology"},{"issue":"6","key":"pone.0258199.ref060","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/jnc.14227","article-title":"16p11.2 deletion syndrome mice perseverate with active coping response to acute stress\u2014rescue by blocking 5-HT2A receptors","volume":"143","author":"CM Panzini","year":"2017","journal-title":"Journal of neurochemistry"},{"issue":"6","key":"pone.0258199.ref061","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/0278-5846(90)90073-P","article-title":"Neurobehavioral studies of forced swimming: the role of learning and memory in the forced swim test","volume":"14","author":"AP West","year":"1990","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"issue":"5","key":"pone.0258199.ref062","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/npp.2017.260","article-title":"Too Depressed to Swim or Too Afraid to Stop? A Reinterpretation of the Forced Swim Test as a Measure of Anxiety-Like Behavior","volume":"43","author":"J Anyan","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"pone.0258199.ref063","first-page":"1","article-title":"Time in the central area of the elevated plus-maze correlates with impulsivity-related measures during an operant task","volume":"15","author":"JL Rico","year":"2016","journal-title":"Universitas Psychologica"},{"issue":"1","key":"pone.0258199.ref064","article-title":"Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder","volume":"13","author":"Ueno Ki","year":"2002","journal-title":"Behavioural Pharmacology"},{"issue":"1","key":"pone.0258199.ref065","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12402-010-0034-y","article-title":"Comparison of SHR, WKY and Wistar rats in different behavioural animal models: effect of dopamine D1 and alpha2 agonists","volume":"3","author":"B Langen","year":"2011","journal-title":"ADHD Attention Deficit and Hyperactivity Disorders"},{"issue":"1","key":"pone.0258199.ref066","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1177\/1754073911421374","article-title":"The Elevated Plus-Maze Test: Differential Psychopharmacology of Anxiety-Related Behavior","volume":"4","author":"CR Pawlak","year":"2012","journal-title":"Emotion Review"},{"key":"pone.0258199.ref067","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.bbr.2014.08.026","article-title":"The spontaneously hypertensive rat\/Izm (SHR\/Izm) shows attention deficit\/hyperactivity disorder-like behaviors but without impulsive behavior: Therapeutic implications of low-dose methylphenidate","volume":"274","author":"Y Kishikawa","year":"2014","journal-title":"Behavioural Brain Research"},{"issue":"3","key":"pone.0258199.ref068","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1080\/24750573.2018.1449184","article-title":"The relation between serum Toxoplasma gondii IgG antibody in children and ADHD and its severity","volume":"29","author":"\u0130 Akaltun","year":"2019","journal-title":"Psychiatry and Clinical Psychopharmacology"},{"key":"pone.0258199.ref069","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuroscience.2011.12.051","article-title":"Sex-specific changes in gene expression and behavior induced by chronic Toxoplasma infection in mice","volume":"206","author":"J Xiao","year":"2012","journal-title":"Neuroscience"},{"issue":"Pt 1","key":"pone.0258199.ref070","first-page":"113","article-title":"Toxoplasma gondii infection and behaviour\u2014location, location, location?","volume":"216","author":"GA McConkey","year":"2012","journal-title":"The Journal of experimental biology"},{"issue":"11","key":"pone.0258199.ref071","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3390\/microorganisms7110573","article-title":"Kinematic Locomotion Changes in C57BL\/6 Mice Infected with Toxoplasma Strain ME49","volume":"7","author":"MdlL Galv\u00e1n-Ram\u00edrez","year":"2019","journal-title":"Microorganisms"},{"key":"pone.0258199.ref072","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.bbi.2013.11.012","article-title":"Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long\u2013Evans rats","volume":"37","author":"AK Evans","year":"2014","journal-title":"Brain, Behavior, and Immunity"},{"issue":"12","key":"pone.0258199.ref073","doi-asserted-by":"crossref","first-page":"e28925","DOI":"10.1371\/journal.pone.0028925","article-title":"The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: implications for the behavioral manipulation hypothesis","volume":"6","author":"M Berenreiterov\u00e1","year":"2011","journal-title":"PloS one"},{"issue":"6","key":"pone.0258199.ref074","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1007\/s11920-012-0322-7","article-title":"Where in the brain is depression?","volume":"14","author":"M Pandya","year":"2012","journal-title":"Current psychiatry reports"},{"key":"pone.0258199.ref075","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1590\/1516-4446-2018-0108","article-title":"Structural and functional neuroimaging studies in generalized anxiety disorder: a systematic review","volume":"41","author":"D Madonna","year":"2019","journal-title":"Brazilian Journal of Psychiatry"},{"issue":"4","key":"pone.0258199.ref076","doi-asserted-by":"crossref","first-page":"e0175433","DOI":"10.1371\/journal.pone.0175433","article-title":"The brain anatomy of attention-deficit\/hyperactivity disorder in young adults\u2014a magnetic resonance imaging study","volume":"12","author":"J-G Gehricke","year":"2017","journal-title":"PloS one"},{"issue":"4","key":"pone.0258199.ref077","doi-asserted-by":"crossref","first-page":"e0250079","DOI":"10.1371\/journal.pone.0250079","article-title":"Rosuvastatin revert memory impairment and anxiogenic-like effect in mice infected with the chronic ME-49 strain of Toxoplasma gondii","volume":"16","author":"FF Evangelista","year":"2021","journal-title":"PLoS One"},{"issue":"12","key":"pone.0258199.ref078","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.1128\/AAC.48.12.4848-4854.2004","article-title":"Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis","volume":"48","author":"IR Dunay","year":"2004","journal-title":"Antimicrob Agents Chemother"},{"issue":"10","key":"pone.0258199.ref079","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1086\/501360","article-title":"Outcome of treatment for congenital toxoplasmosis, 1981\u20132004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study","volume":"42","author":"R McLeod","year":"2006","journal-title":"Clin Infect Dis"},{"issue":"5","key":"pone.0258199.ref080","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/S0022-3476(73)80068-X","article-title":"Intellectual deficits in children born with subclinical congenital toxoplasmosis: a preliminary report","volume":"82","author":"SA Saxon","year":"1973","journal-title":"J Pediatr"},{"issue":"5","key":"pone.0258199.ref081","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1007\/s00401-001-0491-7","article-title":"Chemokines are differentially expressed by astrocytes, microglia and inflammatory leukocytes in Toxoplasma encephalitis and critically regulated by interferon-gamma","volume":"103","author":"A Strack","year":"2002","journal-title":"Acta Neuropathol"},{"issue":"1","key":"pone.0258199.ref082","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.nbd.2009.07.031","article-title":"The blood\u2013brain barrier and immune function and dysfunction","volume":"37","author":"WA Banks","year":"2010","journal-title":"Neurobiology of Disease"},{"issue":"6","key":"pone.0258199.ref083","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2565","article-title":"Regulation of innate immune responses in the brain","volume":"9","author":"S Rivest","year":"2009","journal-title":"Nature Reviews Immunology"},{"issue":"3","key":"pone.0258199.ref084","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0928-8244(03)00279-7","article-title":"From cells to signaling cascades: manipulation of innate immunity by Toxoplasma gondii","volume":"39","author":"EY Denkers","year":"2003","journal-title":"FEMS immunology and medical microbiology"},{"issue":"7","key":"pone.0258199.ref085","doi-asserted-by":"crossref","first-page":"4171","DOI":"10.1128\/IAI.71.7.4171-4174.2003","article-title":"Different strains of Toxoplasma gondii induce different cytokine responses in CBA\/Ca mice","volume":"71","author":"FG Araujo","year":"2003","journal-title":"Infect Immun"},{"key":"pone.0258199.ref086","first-page":"83","volume-title":"Toxoplasmose & Toxoplasma gondii","author":"J Lannes-Vieira","year":"2014"},{"issue":"7","key":"pone.0258199.ref087","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.4049\/jimmunol.151.7.3672","article-title":"Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation","volume":"151","author":"RT Gazzinelli","year":"1993","journal-title":"J Immunol"},{"issue":"6","key":"pone.0258199.ref088","doi-asserted-by":"crossref","first-page":"3686","DOI":"10.4049\/jimmunol.172.6.3686","article-title":"Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype","volume":"172","author":"PM Robben","year":"2004","journal-title":"J Immunol"},{"issue":"1","key":"pone.0258199.ref089","doi-asserted-by":"crossref","first-page":"350","DOI":"10.4049\/jimmunol.1004144","article-title":"IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii","volume":"187","author":"JS Silver","year":"2011","journal-title":"J Immunol"},{"issue":"6","key":"pone.0258199.ref090","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1128\/iai.65.6.2339-2345.1997","article-title":"Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice","volume":"65","author":"Y Suzuki","year":"1997","journal-title":"Infect Immun"},{"issue":"11","key":"pone.0258199.ref091","doi-asserted-by":"crossref","first-page":"6954","DOI":"10.4049\/jimmunol.172.11.6954","article-title":"Toxoplasma gondii triggers myeloid differentiation factor 88-dependent IL-12 and chemokine ligand 2 (monocyte chemoattractant protein 1) responses using distinct parasite molecules and host receptors","volume":"172","author":"L Del Rio","year":"2004","journal-title":"J Immunol"},{"key":"pone.0258199.ref092","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.bbrep.2016.05.008","article-title":"Induction of IL-10-producing regulatory B cells following Toxoplasma gondii infection is important to the cyst formation","volume":"7","author":"Y-I Jeong","year":"2016","journal-title":"Biochemistry and biophysics reports"},{"issue":"3","key":"pone.0258199.ref093","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2353\/ajpath.2008.080129","article-title":"CCR2 receptor is essential to activate microbicidal mechanisms to control Toxoplasma gondii infection in the central nervous system","volume":"173","author":"L Benevides","year":"2008","journal-title":"Am J Pathol"},{"issue":"7","key":"pone.0258199.ref094","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.biopsych.2014.01.005","article-title":"Peripheral Inflammation Acutely Impairs Human Spatial Memory via Actions on Medial Temporal Lobe Glucose Metabolism","volume":"76","author":"NA Harrison","year":"2014","journal-title":"Biological Psychiatry"},{"issue":"3","key":"pone.0258199.ref095","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.exppara.2010.02.002","article-title":"Inflammatory changes in the central nervous system are associated with behavioral impairment in Plasmodium berghei (strain ANKA)-infected mice","volume":"125","author":"N Lacerda-Queiroz","year":"2010","journal-title":"Experimental parasitology"},{"issue":"4","key":"pone.0258199.ref096","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.biopsych.2008.07.024","article-title":"Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease","volume":"65","author":"C Cunningham","year":"2009","journal-title":"Biological Psychiatry"},{"key":"pone.0258199.ref097","doi-asserted-by":"crossref","first-page":"278531","DOI":"10.1155\/2009\/278531","article-title":"Breaching the Blood-Brain Barrier as a Gate to Psychiatric Disorder","volume":"2009","author":"H Shalev","year":"2009","journal-title":"Cardiovascular Psychiatry and Neurology"},{"issue":"11","key":"pone.0258199.ref098","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1016\/j.ajpath.2018.07.007","article-title":"The Neurotropic Parasite Toxoplasma gondii Induces Sustained Neuroinflammation with Microvascular Dysfunction in Infected Mice","volume":"188","author":"V Estato","year":"2018","journal-title":"The American journal of pathology"},{"issue":"Suppl 6","key":"pone.0258199.ref099","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1528-1167.2012.03701.x","article-title":"Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis","volume":"53","author":"SY Kim","year":"2012","journal-title":"Epilepsia"},{"issue":"9","key":"pone.0258199.ref100","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21093344","article-title":"Mechanisms of Blood\u2013Brain Barrier Dysfunction in Traumatic Brain Injury","volume":"21","author":"A Cash","year":"2020","journal-title":"International Journal of Molecular Sciences"},{"issue":"7","key":"pone.0258199.ref101","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1177\/0271678X16670922","article-title":"Stroke-induced blood-brain barrier breakdown along the vascular tree\u2014No preferential affection of arteries in different animal models and in humans. Journal of cerebral blood flow and metabolism: official journal of the","volume":"37","author":"M Krueger","year":"2017","journal-title":"International Society of Cerebral Blood Flow and Metabolism"},{"issue":"521","key":"pone.0258199.ref102","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaw8954","article-title":"Paroxysmal slow cortical activity in Alzheimer\u2019s disease and epilepsy is associated with blood-brain barrier dysfunction","volume":"11","author":"DZ Milikovsky","year":"2019","journal-title":"Sci Transl Med"},{"issue":"1","key":"pone.0258199.ref103","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/s41398-020-01054-3","article-title":"Blood-brain barrier associated tight junction disruption is a hallmark feature of major psychiatric disorders","volume":"10","author":"C Greene","year":"2020","journal-title":"Translational Psychiatry"},{"issue":"12","key":"pone.0258199.ref104","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1038\/s41593-017-0010-3","article-title":"Social stress induces neurovascular pathology promoting depression","volume":"20","author":"C Menard","year":"2017","journal-title":"Nature neuroscience"},{"issue":"1","key":"pone.0258199.ref105","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jad.2007.02.018","article-title":"Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder","volume":"104","author":"Y-K Kim","year":"2007","journal-title":"Journal of Affective Disorders"},{"issue":"6","key":"pone.0258199.ref106","doi-asserted-by":"crossref","first-page":"e0197267","DOI":"10.1371\/journal.pone.0197267","article-title":"Changes in the serum levels of inflammatory cytokines in antidepressant drug-na\u00efve patients with major depression","volume":"13","author":"W Zou","year":"2018","journal-title":"PloS one"},{"issue":"7","key":"pone.0258199.ref107","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.biopsych.2011.04.013","article-title":"Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects","volume":"70","author":"BJ Miller","year":"2011","journal-title":"Biol Psychiatry"},{"key":"pone.0258199.ref108","article-title":"Serum cytokines in paediatric neuropsychiatric syndromes: focus on Attention Deficit Hyperactivity Disorder","author":"R Donfrancesco","year":"2016","journal-title":"Minerva Pediatr"},{"issue":"2","key":"pone.0258199.ref109","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1177\/0883073818809831","article-title":"Serum Interleukin-6 Level in Children With Attention-Deficit Hyperactivity Disorder (ADHD)","volume":"34","author":"AH Darwish","year":"2019","journal-title":"J Child Neurol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258199","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T04:53:09Z","timestamp":1673412789000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258199"}},"subtitle":[],"editor":[{"given":"Slava","family":"Rom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,5]]},"references-count":109,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0258199","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,5]]}}}