{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:28:07Z","timestamp":1785025687377,"version":"3.55.0"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000025","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH058616"],"award-info":[{"award-number":["MH058616"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH058616"],"award-info":[{"award-number":["MH058616"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH099085"],"award-info":[{"award-number":["MH099085"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Environmental risk factors contribute to autism spectrum disorders (ASD) etiology. In particular, prenatal exposure to the highly teratogenic anticonvulsant valproic acid (VPA) significantly increases ASD prevalence. Although significant discoveries on the embryopathology of VPA have been reported, its effects on the ability to form enduring social attachment\u2014characteristic of ASD but uncommonly displayed by rats and mice\u2014remains unknown. We aimed to examine the effects of prenatal VPA exposure in the social, monogamous prairie voles (<jats:italic>Microtus ochrogaster<\/jats:italic>). Compared to prenatal vehicle-exposed controls, prenatal VPA-exposed prairie voles had lower body weight throughout postnatal development, engaged in fewer social affiliative behaviors in a familial context, exhibited less social interactions with novel conspecifics, and showed enhanced anxiety-like behavior. Along these behavioral deficits, prenatal VPA exposure downregulated prefrontal cortex vasopressin receptor (V1aR) and methyl CpG-binding protein 2 (MeCP2) mRNA expression, but did not alter spine density in adults. Remarkably, adult social bonding behaviors, such as partner preference formation and selective aggression, were not disrupted by prenatal VPA exposure. Collectively, these studies suggest that, in this animal model, VPA alters only certain behavioral domains such as sex-naive anxiety and affiliative behaviors, but does not alter other domains such as social bonding with opposite sex individuals.<\/jats:p>","DOI":"10.1038\/s41598-019-39014-7","type":"journal-article","created":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T11:04:12Z","timestamp":1550747052000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Consequences of prenatal exposure to valproic acid in the socially monogamous prairie voles"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2020-2390","authenticated-orcid":false,"given":"L.","family":"Sailer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0121-5807","authenticated-orcid":false,"given":"F.","family":"Duclot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Kabbaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"39014_CR1","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.biopsych.2010.05.028","volume":"68","author":"TL Bale","year":"2010","unstructured":"Bale, T. L. et al. Early life programming and neurodevelopmental disorders. Biological psychiatry 68, 314\u2013319, https:\/\/doi.org\/10.1016\/j.biopsych.2010.05.028 (2010).","journal-title":"Biological psychiatry"},{"key":"39014_CR2","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1517\/14740338.4.2.345","volume":"4","author":"R Alsdorf","year":"2005","unstructured":"Alsdorf, R. & Wyszynski, D. F. Teratogenicity of sodium valproate. Expert Opin Drug Saf 4, 345\u2013353 (2005).","journal-title":"Expert Opin Drug Saf"},{"key":"39014_CR3","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1212\/01.wnl.0000339399.64213.1a","volume":"71","author":"RL Bromley","year":"2008","unstructured":"Bromley, R. L. et al. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 71, 1923\u20131924, https:\/\/doi.org\/10.1212\/01.wnl.0000339399.64213.1a (2008).","journal-title":"Neurology"},{"key":"39014_CR4","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.seizure.2009.11.008","volume":"19","author":"G Mawer","year":"2010","unstructured":"Mawer, G. et al. Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study. Seizure 19, 112\u2013119, https:\/\/doi.org\/10.1016\/j.seizure.2009.11.008 (2010).","journal-title":"Seizure"},{"key":"39014_CR5","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1212\/WNL.0b013e318250d824","volume":"78","author":"KJ Meador","year":"2012","unstructured":"Meador, K. J. et al. Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. Neurology 78, 1207\u20131214, https:\/\/doi.org\/10.1212\/WNL.0b013e318250d824 (2012).","journal-title":"Neurology"},{"key":"39014_CR6","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1017\/S1092852913000990","volume":"19","author":"S Gentile","year":"2014","unstructured":"Gentile, S. Risks of neurobehavioral teratogenicity associated with prenatal exposure to valproate monotherapy: a systematic review with regulatory repercussions. CNS Spectr 19, 305\u2013315, https:\/\/doi.org\/10.1017\/S1092852913000990 (2014).","journal-title":"CNS Spectr"},{"key":"39014_CR7","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1001\/jama.2013.2270","volume":"309","author":"J Christensen","year":"2013","unstructured":"Christensen, J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309, 1696\u20131703, https:\/\/doi.org\/10.1001\/jama.2013.2270 (2013).","journal-title":"JAMA"},{"key":"39014_CR8","doi-asserted-by":"publisher","unstructured":"Elvir, L., Duclot, F., Wang, Z. & Kabbaj, M. Epigenetic regulation of motivated behaviors by histone deacetylase inhibitors. Neurosci Biobehav Rev, https:\/\/doi.org\/10.1016\/j.neubiorev.2017.09.030 (2017).","DOI":"10.1016\/j.neubiorev.2017.09.030"},{"key":"39014_CR9","doi-asserted-by":"publisher","first-page":"8288","DOI":"10.1523\/JNEUROSCI.0097-09.2009","volume":"29","author":"MW Akhtar","year":"2009","unstructured":"Akhtar, M. W. et al. Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function. J Neurosci 29, 8288\u20138297, https:\/\/doi.org\/10.1523\/JNEUROSCI.0097-09.2009 (2009).","journal-title":"J Neurosci"},{"key":"39014_CR10","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/j.ijdevneu.2013.09.002","volume":"31","author":"OS Cohen","year":"2013","unstructured":"Cohen, O. S., Varlinskaya, E. I., Wilson, C. A., Glatt, S. J. & Mooney, S. M. Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats. Int J Dev Neurosci 31, 740\u2013750, https:\/\/doi.org\/10.1016\/j.ijdevneu.2013.09.002 (2013).","journal-title":"Int J Dev Neurosci"},{"key":"39014_CR11","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.bbr.2013.09.049","volume":"257","author":"RX Moldrich","year":"2013","unstructured":"Moldrich, R. X. et al. Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behavioural brain research 257, 253\u2013264, https:\/\/doi.org\/10.1016\/j.bbr.2013.09.049 (2013).","journal-title":"Behavioural brain research"},{"key":"39014_CR12","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1111\/jnc.12147","volume":"124","author":"KC Kim","year":"2013","unstructured":"Kim, K. C. et al. Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder. J Neurochem 124, 832\u2013843, https:\/\/doi.org\/10.1111\/jnc.12147 (2013).","journal-title":"J Neurochem"},{"key":"39014_CR13","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.neuroscience.2013.03.030","volume":"241","author":"ME Bringas","year":"2013","unstructured":"Bringas, M. E., Carvajal-Flores, F. N., Lopez-Ramirez, T. A., Atzori, M. & Flores, G. Rearrangement of the dendritic morphology in limbic regions and altered exploratory behavior in a rat model of autism spectrum disorder. Neuroscience 241, 170\u2013187, https:\/\/doi.org\/10.1016\/j.neuroscience.2013.03.030 (2013).","journal-title":"Neuroscience"},{"key":"39014_CR14","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1017\/S1461145711001714","volume":"16","author":"S Kataoka","year":"2013","unstructured":"Kataoka, S. et al. Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 16, 91\u2013103, https:\/\/doi.org\/10.1017\/S1461145711001714 (2013).","journal-title":"Int J Neuropsychopharmacol"},{"key":"39014_CR15","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.ejphar.2014.01.050","volume":"727","author":"AG Foley","year":"2014","unstructured":"Foley, A. G., Cassidy, A. W. & Regan, C. M. Pentyl-4-yn-VPA, a histone deacetylase inhibitor, ameliorates deficits in social behavior and cognition in a rodent model of autism spectrum disorders. Eur J Pharmacol 727, 80\u201386, https:\/\/doi.org\/10.1016\/j.ejphar.2014.01.050 (2014).","journal-title":"Eur J Pharmacol"},{"key":"39014_CR16","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/s12035-014-8987-z","volume":"53","author":"KC Kim","year":"2016","unstructured":"Kim, K. C. et al. MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism. Mol Neurobiol 53, 40\u201356, https:\/\/doi.org\/10.1007\/s12035-014-8987-z (2016).","journal-title":"Mol Neurobiol"},{"key":"39014_CR17","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.psyneuen.2008.02.011","volume":"33","author":"T Schneider","year":"2008","unstructured":"Schneider, T. et al. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology 33, 728\u2013740, https:\/\/doi.org\/10.1016\/j.psyneuen.2008.02.011 (2008).","journal-title":"Psychoneuroendocrinology"},{"key":"39014_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss6706a1","volume":"67","author":"J Baio","year":"2018","unstructured":"Baio, J. et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ 67, 1\u201323, https:\/\/doi.org\/10.15585\/mmwr.ss6706a1 (2018).","journal-title":"MMWR Surveill Summ"},{"key":"39014_CR19","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1017\/S0012162205001076","volume":"47","author":"AD Rasalam","year":"2005","unstructured":"Rasalam, A. D. et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 47, 551\u2013555 (2005).","journal-title":"Dev Med Child Neurol"},{"key":"39014_CR20","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/0018-506X(92)90004-F","volume":"26","author":"JR Williams","year":"1992","unstructured":"Williams, J. R., Catania, K. C. & Carter, C. S. Development of partner preferences in female prairie voles (Microtus ochrogaster): the role of social and sexual experience. Hormones and behavior 26, 339\u2013349 (1992).","journal-title":"Hormones and behavior"},{"key":"39014_CR21","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1002\/dev.20498","volume":"53","author":"TH Ahern","year":"2011","unstructured":"Ahern, T. H., Hammock, E. A. & Young, L. J. Parental division of labor, coordination, and the effects of family structure on parenting in monogamous prairie voles (Microtus ochrogaster). Dev Psychobiol 53, 118\u2013131, https:\/\/doi.org\/10.1002\/dev.20498 (2011).","journal-title":"Dev Psychobiol"},{"key":"39014_CR22","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/cphy.c150055","volume":"7","author":"M Tabbaa","year":"2016","unstructured":"Tabbaa, M., Paedae, B., Liu, Y. & Wang, Z. Neuropeptide Regulation of Social Attachment: The Prairie Vole Model. Compr Physiol 7, 81\u2013104, https:\/\/doi.org\/10.1002\/cphy.c150055 (2016).","journal-title":"Compr Physiol"},{"key":"39014_CR23","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.conb.2016.04.011","volume":"38","author":"K Gobrogge","year":"2016","unstructured":"Gobrogge, K. & Wang, Z. The ties that bond: neurochemistry of attachment in voles. Current opinion in neurobiology 38, 80\u201388, https:\/\/doi.org\/10.1016\/j.conb.2016.04.011 (2016).","journal-title":"Current opinion in neurobiology"},{"key":"39014_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.yfrne.2015.04.003","volume":"40","author":"KM Dumais","year":"2016","unstructured":"Dumais, K. M. & Veenema, A. H. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 40, 1\u201323, https:\/\/doi.org\/10.1016\/j.yfrne.2015.04.003 (2016).","journal-title":"Front Neuroendocrinol"},{"key":"39014_CR25","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.neulet.2005.10.019","volume":"394","author":"MD Smeltzer","year":"2006","unstructured":"Smeltzer, M. D., Curtis, J. T., Aragona, B. J. & Wang, Z. Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles. Neuroscience letters 394, 146\u2013151, https:\/\/doi.org\/10.1016\/j.neulet.2005.10.019 (2006).","journal-title":"Neuroscience letters"},{"key":"39014_CR26","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1006\/hbeh.2001.1691","volume":"40","author":"LJ Young","year":"2001","unstructured":"Young, L. J., Lim, M. M., Gingrich, B. & Insel, T. R. Cellular mechanisms of social attachment. Hormones and behavior 40, 133\u2013138, https:\/\/doi.org\/10.1006\/hbeh.2001.1691 (2001).","journal-title":"Hormones and behavior"},{"key":"39014_CR27","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/S0306-4522(03)00555-4","volume":"121","author":"Y Liu","year":"2003","unstructured":"Liu, Y. & Wang, Z. X. Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience 121, 537\u2013544 (2003).","journal-title":"Neuroscience"},{"key":"39014_CR28","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1037\/0735-7044.113.5.1071","volume":"113","author":"MM Cho","year":"1999","unstructured":"Cho, M. M., DeVries, A. C., Williams, J. R. & Carter, C. S. The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster). Behavioral neuroscience 113, 1071\u20131079 (1999).","journal-title":"Behavioral neuroscience"},{"key":"39014_CR29","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1037\/a0018094","volume":"124","author":"ZR Donaldson","year":"2010","unstructured":"Donaldson, Z. R., Spiegel, L. & Young, L. J. Central vasopressin V1a receptor activation is independently necessary for both partner preference formation and expression in socially monogamous male prairie voles. Behavioral neuroscience 124, 159\u2013163, https:\/\/doi.org\/10.1037\/a0018094 (2010).","journal-title":"Behavioral neuroscience"},{"key":"39014_CR30","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nature02539","volume":"429","author":"MM Lim","year":"2004","unstructured":"Lim, M. M. et al. Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature 429, 754\u2013757, https:\/\/doi.org\/10.1038\/nature02539 (2004).","journal-title":"Nature"},{"key":"39014_CR31","doi-asserted-by":"publisher","first-page":"970","DOI":"10.3389\/fnhum.2014.00970","volume":"8","author":"S Martinez-Sanchis","year":"2014","unstructured":"Martinez-Sanchis, S. Neurobiological foundations of multisensory integration in people with autism spectrum disorders: the role of the medial prefrontal cortex. Front Hum Neurosci 8, 970, https:\/\/doi.org\/10.3389\/fnhum.2014.00970 (2014).","journal-title":"Front Hum Neurosci"},{"key":"39014_CR32","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3389\/fnmol.2016.00150","volume":"9","author":"E Lauber","year":"2016","unstructured":"Lauber, E., Filice, F. & Schwaller, B. Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice. Frontiers in molecular neuroscience 9, 150, https:\/\/doi.org\/10.3389\/fnmol.2016.00150 (2016).","journal-title":"Frontiers in molecular neuroscience"},{"key":"39014_CR33","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.brainresbull.2012.01.011","volume":"87","author":"L Sui","year":"2012","unstructured":"Sui, L. & Chen, M. Prenatal exposure to valproic acid enhances synaptic plasticity in the medial prefrontal cortex and fear memories. Brain Res Bull 87, 556\u2013563, https:\/\/doi.org\/10.1016\/j.brainresbull.2012.01.011 (2012).","journal-title":"Brain Res Bull"},{"key":"39014_CR34","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1001\/jama.2011.1638","volume":"306","author":"E Courchesne","year":"2011","unstructured":"Courchesne, E. et al. Neuron number and size in prefrontal cortex of children with autism. JAMA 306, 2001\u20132010, https:\/\/doi.org\/10.1001\/jama.2011.1638 (2011).","journal-title":"JAMA"},{"key":"39014_CR35","doi-asserted-by":"publisher","first-page":"609","DOI":"10.3389\/fnhum.2013.00609","volume":"7","author":"B Zikopoulos","year":"2013","unstructured":"Zikopoulos, B. & Barbas, H. Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci 7, 609, https:\/\/doi.org\/10.3389\/fnhum.2013.00609 (2013).","journal-title":"Front Hum Neurosci"},{"key":"39014_CR36","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3389\/neuro.04.004.2008","volume":"2","author":"T Rinaldi","year":"2008","unstructured":"Rinaldi, T., Perrodin, C. & Markram, H. Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism. Front Neural Circuits 2, 4, https:\/\/doi.org\/10.3389\/neuro.04.004.2008 (2008).","journal-title":"Front Neural Circuits"},{"key":"39014_CR37","doi-asserted-by":"publisher","unstructured":"Mahmood, U. et al. Dendritic spine anomalies and PTEN alterations in a mouse model of VPA-induced autism spectrum disorder. Pharmacol Res, https:\/\/doi.org\/10.1016\/j.phrs.2017.08.006 (2017).","DOI":"10.1016\/j.phrs.2017.08.006"},{"key":"39014_CR38","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.brainres.2011.06.015","volume":"1408","author":"V Bambini-Junior","year":"2011","unstructured":"Bambini-Junior, V. et al. Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain research 1408, 8\u201316, https:\/\/doi.org\/10.1016\/j.brainres.2011.06.015 (2011).","journal-title":"Brain research"},{"key":"39014_CR39","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1126\/science.286.5442.1155","volume":"286","author":"D Francis","year":"1999","unstructured":"Francis, D., Diorio, J., Liu, D. & Meaney, M. J. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286, 1155\u20131158 (1999).","journal-title":"Science"},{"key":"39014_CR40","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/npp.2012.149","volume":"38","author":"TY Zhang","year":"2013","unstructured":"Zhang, T. Y., Labonte, B., Wen, X. L., Turecki, G. & Meaney, M. J. Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 38, 111\u2013123, https:\/\/doi.org\/10.1038\/npp.2012.149 (2013).","journal-title":"Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology"},{"key":"39014_CR41","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1038\/npp.2015.19","volume":"40","author":"HB Nguyen","year":"2015","unstructured":"Nguyen, H. B., Bagot, R. C., Diorio, J., Wong, T. P. & Meaney, M. J. Maternal care differentially affects neuronal excitability and synaptic plasticity in the dorsal and ventral hippocampus. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 40, 1590\u20131599, https:\/\/doi.org\/10.1038\/npp.2015.19 (2015).","journal-title":"Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology"},{"key":"39014_CR42","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.neuroscience.2016.12.011","volume":"343","author":"M Tabbaa","year":"2017","unstructured":"Tabbaa, M., Lei, K., Liu, Y. & Wang, Z. Paternal deprivation affects social behaviors and neurochemical systems in the offspring of socially monogamous prairie voles. Neuroscience 343, 284\u2013297, https:\/\/doi.org\/10.1016\/j.neuroscience.2016.12.011 (2017).","journal-title":"Neuroscience"},{"key":"39014_CR43","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1111\/j.1601-183X.2004.00071.x","volume":"3","author":"JJ Nadler","year":"2004","unstructured":"Nadler, J. J. et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav 3, 303\u2013314, https:\/\/doi.org\/10.1111\/j.1601-183X.2004.00071.x (2004).","journal-title":"Genes Brain Behav"},{"key":"39014_CR44","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.neulet.2009.02.064","volume":"454","author":"Y Pan","year":"2009","unstructured":"Pan, Y., Liu, Y., Young, K. A., Zhang, Z. & Wang, Z. Post-weaning social isolation alters anxiety-related behavior and neurochemical gene expression in the brain of male prairie voles. Neuroscience letters 454, 67\u201371, https:\/\/doi.org\/10.1016\/j.neulet.2009.02.064 (2009).","journal-title":"Neuroscience letters"},{"key":"39014_CR45","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.bbr.2014.02.016","volume":"265","author":"P Sun","year":"2014","unstructured":"Sun, P., Smith, A. S., Lei, K., Liu, Y. & Wang, Z. Breaking bonds in male prairie vole: long-term effects on emotional and social behavior, physiology, and neurochemistry. Behavioural brain research 265, 22\u201331, https:\/\/doi.org\/10.1016\/j.bbr.2014.02.016 (2014).","journal-title":"Behavioural brain research"},{"key":"39014_CR46","unstructured":"Paxinos, G. & Watson, C. The rat brain in stereotaxic coordinates. 6th edn, (Academic Press\/Elsevier, 2007)."},{"key":"39014_CR47","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.yhbeh.2016.04.001","volume":"81","author":"F Duclot","year":"2016","unstructured":"Duclot, F. et al. Trichostatin A (TSA) facilitates formation of partner preference in male prairie voles (Microtus ochrogaster). Hormones and behavior 81, 68\u201373, https:\/\/doi.org\/10.1016\/j.yhbeh.2016.04.001 (2016).","journal-title":"Hormones and behavior"},{"key":"39014_CR48","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/nn.3932","volume":"18","author":"JW Koo","year":"2015","unstructured":"Koo, J. W. et al. Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nature neuroscience 18, 415\u2013422, https:\/\/doi.org\/10.1038\/nn.3932 (2015).","journal-title":"Nature neuroscience"},{"key":"39014_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11025","volume":"7","author":"HT Rube","year":"2016","unstructured":"Rube, H. T. et al. Sequence features accurately predict genome-wide MeCP2 binding in vivo. Nat Commun 7, 11025, https:\/\/doi.org\/10.1038\/ncomms11025 (2016).","journal-title":"Nat Commun"},{"key":"39014_CR50","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.biopsych.2015.12.025","volume":"80","author":"A Sarkar","year":"2016","unstructured":"Sarkar, A. & Kabbaj, M. Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats. Biological psychiatry 80, 448\u2013456, https:\/\/doi.org\/10.1016\/j.biopsych.2015.12.025 (2016).","journal-title":"Biological psychiatry"},{"key":"39014_CR51","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.yfrne.2010.07.006","volume":"32","author":"KA Young","year":"2011","unstructured":"Young, K. A., Gobrogge, K. L., Liu, Y. & Wang, Z. The neurobiology of pair bonding: insights from a socially monogamous rodent. Front Neuroendocrinol 32, 53\u201369, https:\/\/doi.org\/10.1016\/j.yfrne.2010.07.006 (2011).","journal-title":"Front Neuroendocrinol"},{"key":"39014_CR52","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/B978-0-12-380858-5.00003-4","volume":"75","author":"KL Gobrogge","year":"2011","unstructured":"Gobrogge, K. L. & Wang, Z. W. Genetics of aggression in voles. Adv Genet 75, 121\u2013150, https:\/\/doi.org\/10.1016\/B978-0-12-380858-5.00003-4 (2011).","journal-title":"Adv Genet"},{"key":"39014_CR53","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.biopsych.2016.02.013","volume":"81","author":"KL Gobrogge","year":"2017","unstructured":"Gobrogge, K. L., Jia, X., Liu, Y. & Wang, Z. Neurochemical Mediation of Affiliation and Aggression Associated With Pair-Bonding. Biological psychiatry 81, 231\u2013242, https:\/\/doi.org\/10.1016\/j.biopsych.2016.02.013 (2017).","journal-title":"Biological psychiatry"},{"key":"39014_CR54","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1097\/YCO.0000000000000133","volume":"28","author":"RA Vasa","year":"2015","unstructured":"Vasa, R. A. & Mazurek, M. O. An update on anxiety in youth with autism spectrum disorders. Curr Opin Psychiatry 28, 83\u201390, https:\/\/doi.org\/10.1097\/YCO.0000000000000133 (2015).","journal-title":"Curr Opin Psychiatry"},{"key":"39014_CR55","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1038\/sj.npp.1301453","volume":"33","author":"K Markram","year":"2008","unstructured":"Markram, K., Rinaldi, T., La Mendola, D., Sandi, C. & Markram, H. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 33, 901\u2013912, https:\/\/doi.org\/10.1038\/sj.npp.1301453 (2008).","journal-title":"Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology"},{"key":"39014_CR56","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1254\/jphs.12025SC","volume":"118","author":"Y Hara","year":"2012","unstructured":"Hara, Y. et al. Effect of prenatal valproic acid exposure on cortical morphology in female mice. J Pharmacol Sci 118, 543\u2013546 (2012).","journal-title":"J Pharmacol Sci"},{"key":"39014_CR57","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.ajhg.2012.03.017","volume":"90","author":"D Sato","year":"2012","unstructured":"Sato, D. et al. SHANK1 Deletions in Males with Autism Spectrum Disorder. Am J Hum Genet 90, 879\u2013887, https:\/\/doi.org\/10.1016\/j.ajhg.2012.03.017 (2012).","journal-title":"Am J Hum Genet"},{"key":"39014_CR58","doi-asserted-by":"publisher","first-page":"14615","DOI":"10.1073\/pnas.0803652105","volume":"105","author":"L Alonso-Nanclares","year":"2008","unstructured":"Alonso-Nanclares, L., Gonzalez-Soriano, J., Rodriguez, J. R. & DeFelipe, J. Gender differences in human cortical synaptic density. Proceedings of the National Academy of Sciences of the United States of America 105, 14615\u201314619, https:\/\/doi.org\/10.1073\/pnas.0803652105 (2008).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"39014_CR59","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1126\/science.1153252","volume":"320","author":"M Chahrour","year":"2008","unstructured":"Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224\u20131229, https:\/\/doi.org\/10.1126\/science.1153252 (2008).","journal-title":"Science"},{"key":"39014_CR60","doi-asserted-by":"publisher","first-page":"e26077","DOI":"10.1371\/journal.pone.0026077","volume":"6","author":"MV Mehta","year":"2011","unstructured":"Mehta, M. V., Gandal, M. J. & Siegel, S. J. mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism. PLoS One 6, e26077, https:\/\/doi.org\/10.1371\/journal.pone.0026077 (2011).","journal-title":"PLoS One"},{"key":"39014_CR61","doi-asserted-by":"publisher","first-page":"13501","DOI":"10.1073\/pnas.0704391104","volume":"104","author":"T Rinaldi","year":"2007","unstructured":"Rinaldi, T., Kulangara, K., Antoniello, K. & Markram, H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proceedings of the National Academy of Sciences of the United States of America 104, 13501\u201313506, https:\/\/doi.org\/10.1073\/pnas.0704391104 (2007).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"39014_CR62","doi-asserted-by":"publisher","DOI":"10.1038\/srep27400","volume":"6","author":"Y Iijima","year":"2016","unstructured":"Iijima, Y. et al. Distinct Defects in Synaptic Differentiation of Neocortical Neurons in Response to Prenatal Valproate Exposure. Sci Rep 6, 27400, https:\/\/doi.org\/10.1038\/srep27400 (2016).","journal-title":"Sci Rep"},{"key":"39014_CR63","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-017-0149-5","volume":"8","author":"Y Hara","year":"2017","unstructured":"Hara, Y. et al. Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain. Mol Autism 8, 33, https:\/\/doi.org\/10.1186\/s13229-017-0149-5 (2017).","journal-title":"Mol Autism"},{"key":"39014_CR64","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3389\/fnbeh.2013.00021","volume":"7","author":"AM Perkeybile","year":"2013","unstructured":"Perkeybile, A. M., Griffin, L. L. & Bales, K. L. Natural variation in early parental care correlates with social behaviors in adolescent prairie voles (Microtus ochrogaster). Frontiers in behavioral neuroscience 7, 21, https:\/\/doi.org\/10.3389\/fnbeh.2013.00021 (2013).","journal-title":"Frontiers in behavioral neuroscience"},{"key":"39014_CR65","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/sj.npp.1300518","volume":"30","author":"T Schneider","year":"2005","unstructured":"Schneider, T. & Przewlocki, R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 30, 80\u201389, https:\/\/doi.org\/10.1038\/sj.npp.1300518 (2005).","journal-title":"Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology"},{"key":"39014_CR66","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/85899","volume":"27","author":"J Guy","year":"2001","unstructured":"Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27, 322\u2013326, https:\/\/doi.org\/10.1038\/85899 (2001).","journal-title":"Nat Genet"},{"key":"39014_CR67","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1002\/(SICI)1096-9926(199612)54:6<284::AID-TERA3>3.0.CO;2-Z","volume":"54","author":"BC Wlodarczyk","year":"1996","unstructured":"Wlodarczyk, B. C., Craig, J. C., Bennett, G. D., Calvin, J. A. & Finnell, R. H. Valproic acid-induced changes in gene expression during neurulation in a mouse model. Teratology 54, 284\u2013297, doi:10.1002\/(SICI)1096-9926(199612)54:6<284::AID-TERA3>3.0.CO;2-Z (1996).","journal-title":"Teratology"},{"key":"39014_CR68","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.toxlet.2010.12.018","volume":"201","author":"KC Kim","year":"2011","unstructured":"Kim, K. C. et al. The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol Lett 201, 137\u2013142, https:\/\/doi.org\/10.1016\/j.toxlet.2010.12.018 (2011).","journal-title":"Toxicol Lett"},{"key":"39014_CR69","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.tins.2017.11.005","volume":"41","author":"PM Horvath","year":"2018","unstructured":"Horvath, P. M. & Monteggia, L. M. MeCP2 as an Activator of Gene Expression. Trends Neurosci 41, 72\u201374, https:\/\/doi.org\/10.1016\/j.tins.2017.11.005 (2018).","journal-title":"Trends Neurosci"},{"key":"39014_CR70","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10821-0","volume":"7","author":"DA Baribeau","year":"2017","unstructured":"Baribeau, D. A. et al. Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders. Sci Rep 7, 11618, https:\/\/doi.org\/10.1038\/s41598-017-10821-0 (2017).","journal-title":"Sci Rep"},{"key":"39014_CR71","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/FBP.0000000000000316","volume":"28","author":"F Bertelsen","year":"2017","unstructured":"Bertelsen, F. et al. Suppressed play behaviour and decreased oxytocin receptor binding in the amygdala after prenatal exposure to low-dose valproic acid. Behav Pharmacol 28, 450\u2013457, https:\/\/doi.org\/10.1097\/FBP.0000000000000316 (2017).","journal-title":"Behav Pharmacol"},{"key":"39014_CR72","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1523\/JNEUROSCI.4517-09.2010","volume":"30","author":"J Blundell","year":"2010","unstructured":"Blundell, J. et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 30, 2115\u20132129, https:\/\/doi.org\/10.1523\/JNEUROSCI.4517-09.2010 (2010).","journal-title":"J Neurosci"},{"key":"39014_CR73","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1172\/JCI29031","volume":"117","author":"T Sadakata","year":"2007","unstructured":"Sadakata, T. et al. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest 117, 931\u2013943, https:\/\/doi.org\/10.1172\/JCI29031 (2007).","journal-title":"J Clin Invest"},{"key":"39014_CR74","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1523\/JNEUROSCI.3032-07.2008","volume":"28","author":"AY Hung","year":"2008","unstructured":"Hung, A. Y. et al. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J Neurosci 28, 1697\u20131708, https:\/\/doi.org\/10.1523\/JNEUROSCI.3032-07.2008 (2008).","journal-title":"J Neurosci"},{"key":"39014_CR75","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3389\/fncel.2014.00023","volume":"8","author":"HG Martin","year":"2014","unstructured":"Martin, H. G. & Manzoni, O. J. Late onset deficits in synaptic plasticity in the valproic acid rat model of autism. Front Cell Neurosci 8, 23, https:\/\/doi.org\/10.3389\/fncel.2014.00023 (2014).","journal-title":"Front Cell Neurosci"},{"key":"39014_CR76","doi-asserted-by":"publisher","first-page":"13097","DOI":"10.1523\/JNEUROSCI.1341-11.2011","volume":"31","author":"EC Walcott","year":"2011","unstructured":"Walcott, E. C., Higgins, E. A. & Desai, N. S. Synaptic and intrinsic balancing during postnatal development in rat pups exposed to valproic acid in utero. J Neurosci 31, 13097\u201313109, https:\/\/doi.org\/10.1523\/JNEUROSCI.1341-11.2011 (2011).","journal-title":"J Neurosci"},{"key":"39014_CR77","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1016\/j.neuron.2014.07.040","volume":"83","author":"G Tang","year":"2014","unstructured":"Tang, G. et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83, 1131\u20131143, https:\/\/doi.org\/10.1016\/j.neuron.2014.07.040 (2014).","journal-title":"Neuron"},{"key":"39014_CR78","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1159\/000341786","volume":"34","author":"R Mychasiuk","year":"2012","unstructured":"Mychasiuk, R., Richards, S., Nakahashi, A., Kolb, B. & Gibb, R. Effects of rat prenatal exposure to valproic acid on behaviour and neuro-anatomy. Dev Neurosci 34, 268\u2013276, https:\/\/doi.org\/10.1159\/000341786 (2012).","journal-title":"Dev Neurosci"},{"key":"39014_CR79","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0165-0270(94)00125-Z","volume":"57","author":"PV Belichenko","year":"1995","unstructured":"Belichenko, P. V. & Dahlstrom, A. Studies on the 3-dimensional architecture of dendritic spines and varicosities in human cortex by confocal laser scanning microscopy and Lucifer yellow microinjections. J Neurosci Methods 57, 55\u201361 (1995).","journal-title":"J Neurosci Methods"},{"key":"39014_CR80","doi-asserted-by":"publisher","DOI":"10.1038\/srep19796","volume":"6","author":"T Bittolo","year":"2016","unstructured":"Bittolo, T. et al. Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice. Sci Rep 6, 19796, https:\/\/doi.org\/10.1038\/srep19796 (2016).","journal-title":"Sci Rep"},{"key":"39014_CR81","doi-asserted-by":"publisher","first-page":"976164","DOI":"10.1155\/2012\/976164","volume":"2012","author":"CA Chapleau","year":"2012","unstructured":"Chapleau, C. A. et al. Hippocampal CA1 pyramidal neurons of Mecp2 mutant mice show a dendritic spine phenotype only in the presymptomatic stage. Neural Plast 2012, 976164, https:\/\/doi.org\/10.1155\/2012\/976164 (2012).","journal-title":"Neural Plast"},{"key":"39014_CR82","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.bbr.2018.01.015","volume":"342","author":"M Donovan","year":"2018","unstructured":"Donovan, M., Liu, Y. & Wang, Z. Anxiety-like behavior and neuropeptide receptor expression in male and female prairie voles: The effects of stress and social buffering. Behavioural brain research 342, 70\u201378, https:\/\/doi.org\/10.1016\/j.bbr.2018.01.015 (2018).","journal-title":"Behavioural brain research"},{"key":"39014_CR83","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1007\/s10803-006-0159-1","volume":"37","author":"H Hellemans","year":"2007","unstructured":"Hellemans, H., Colson, K., Verbraeken, C., Vermeiren, R. & Deboutte, D. Sexual behavior in high-functioning male adolescents and young adults with autism spectrum disorder. J Autism Dev Disord 37, 260\u2013269, https:\/\/doi.org\/10.1007\/s10803-006-0159-1 (2007).","journal-title":"J Autism Dev Disord"},{"key":"39014_CR84","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1002\/jclp.22319","volume":"73","author":"S Strunz","year":"2017","unstructured":"Strunz, S. et al. Romantic Relationships and Relationship Satisfaction Among Adults With Asperger Syndrome and High-Functioning Autism. J Clin Psychol 73, 113\u2013125, https:\/\/doi.org\/10.1002\/jclp.22319 (2017).","journal-title":"J Clin Psychol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39014-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39014-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39014-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T06:17:24Z","timestamp":1671257844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39014-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,21]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["39014"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-39014-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,21]]},"assertion":[{"value":"20 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 January 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2453"}}