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Thus, little is known about the mechanisms underlying disease progression in females. Here, we searched for potential influences of sex and environment on gestational valproic acid\u2010induced behavioral abnormalities using hippocampal\u2010dependent tasks, and on number and morphometry of microglia of the molecular layer of the dentate gyrus (Mol\u2010DG). We compared male and females BALB\/c control mice with BALB\/c mice gestationally exposed to VPA with regards to exploratory activity and risk assessment in novel environments. Pregnant females and males on gestational day 12.5 received VPA in saline (600\u00a0mg\/kg body weight) or an equal volume of saline by gavage. After weaning, female and male offspring were housed separately either in standard laboratory cages (SE) or enriched cages (EE). At 5\u00a0months of age, these mice underwent behavioral testing and had their brains processed for microglia IBA1 immunolabeling. Compared with control mice, VPA\u2010exposed mice exhibited abnormal behavior in exploring novel environments and assessing risk, and these effects were significantly greater in females than in males and less intense among mice from enriched cages. Three\u2010way ANOVA revealed that environment, sex and valproic acid conditions interacted and altered the behavior results. Microglia number and volume of the Mol\u2010DG were significantly higher in VPA\u2010exposed groups raised in standard cages. The results of counting the intersects of microglia branching on Sholl's circles analyzed with permutational MANOVA, demonstrated that in comparison with males, there was a greater reduction in the number of intersections in females raised in standard cages. These findings suggest that the increased microglia and morphological changes might be associated with behavioral dysfunction in ASD. Moreover, the somatomotor and cognitive stimulation of environmental enrichment started at weaning may be beneficial for reducing behavioral abnormalities and reduction of microglia response in adulthood.<\/jats:p>","DOI":"10.1002\/jdn.10072","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T02:06:29Z","timestamp":1603764389000},"page":"37-50","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["BALB\/c female subjected to valproic acid during gestational period exhibited greater microglial and behavioral changes than male mice: A significant contra intuitive result"],"prefix":"10.1002","volume":"81","author":[{"given":"Alinne Lorrany Gomes","family":"dos Santos","sequence":"first","affiliation":[{"name":"N\u00facleo de Pesquisas em Oncologia Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Oncologia e Ci\u00eancias M\u00e9dicas Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"},{"name":"Laborat\u00f3rio de Investiga\u00e7\u00f5es em Neurodegenera\u00e7\u00e3o e Infec\u00e7\u00e3o Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen Rose Leandro Ponce","family":"de Le\u00e3o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Investiga\u00e7\u00f5es em Neurodegenera\u00e7\u00e3o e Infec\u00e7\u00e3o Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"de Almeida Miranda","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Investiga\u00e7\u00f5es em Neurodegenera\u00e7\u00e3o e Infec\u00e7\u00e3o Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dilza Nazar\u00e9 Colares","family":"de Souza","sequence":"additional","affiliation":[{"name":"N\u00facleo de Pesquisas em Oncologia Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Oncologia e Ci\u00eancias M\u00e9dicas Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"},{"name":"Laborat\u00f3rio de Investiga\u00e7\u00f5es em Neurodegenera\u00e7\u00e3o e Infec\u00e7\u00e3o Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6611-6880","authenticated-orcid":false,"given":"Cristovam Wanderley","family":"Pican\u00e7o Diniz","sequence":"additional","affiliation":[{"name":"N\u00facleo de Pesquisas em Oncologia Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Oncologia e Ci\u00eancias M\u00e9dicas Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"},{"name":"Laborat\u00f3rio de Investiga\u00e7\u00f5es em Neurodegenera\u00e7\u00e3o e Infec\u00e7\u00e3o Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7369-2165","authenticated-orcid":false,"given":"Daniel Guerreiro","family":"Diniz","sequence":"additional","affiliation":[{"name":"N\u00facleo de Pesquisas em Oncologia Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Oncologia e Ci\u00eancias M\u00e9dicas Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"},{"name":"Laborat\u00f3rio de Investiga\u00e7\u00f5es em Neurodegenera\u00e7\u00e3o e Infec\u00e7\u00e3o Hospital Universit\u00e1rio Jo\u00e3o de Barros Barreto Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal do Par\u00e1 Bel\u00e9m Brasil"},{"name":"Laborat\u00f3rio de Microscopia Eletr\u00f4nica Instituto Evandro Chagas Bel\u00e9m Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,11,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(07)63001-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2004.03.014"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1801912115"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2018.05.002"},{"issue":"3","key":"e_1_2_8_6_1","first-page":"236","article-title":"The valproate model of autism","volume":"35","author":"Bossu J. 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