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This study aimed at investigating the possible interaction between maternal separation, a model of early stress, and subsequent neonatal hypoxia\u2010ischemia on emotional behavior and markers of synaptic plasticity in hippocampus. Therefore, rat pups (<jats:italic>N<\/jats:italic>= 60) were maternally separated for a prolonged (MS 180min) or a brief (MS 15min) period during the first six postnatal days, while a control group was left undisturbed. Hypoxia\u2010ischemia was applied to a subgroup of each rearing condition on postnatal day 7. Emotional behavior was examined at three months of age and included assessments of anxiety (elevated plus maze), depression\u2010like behavior (forced swimming) and spontaneous exploration (open field). Synaptic plasticity was evaluated based on BDNF and synaptophysin expression in CA3 and dentate gyrus hippocampal regions. We found that neonatal hypoxia\u2010ischemia caused increased levels of anxiety, depression\u2010like behavior and locomotor activity (ambulation). Higher anxiety levels were also seen in maternally separated rats (MS180min) compared to non\u2010maternally separated rats, but prolonged maternal separation prior to HI did not potentiate the HI\u2010associated effect. No differences among the three rearing conditions were found regarding depression\u2010like behavior or ambulation. Immunohistochemical evaluation of synaptophysin revealed that both prolonged maternal separation (MS180min) and neonatal hypoxia\u2010ischemia significantly reduced its expression in the CA3 and dentate gyrus. Decreases in synaptophysin expression in these areas were not exacerbated in rats that were maternally separated for a prolonged period prior to HI. Regarding BDNF expression, we found a significant decrease in immunoreactivity only in the hypoxic\u2010ischemic rats that were subjected to the prolonged maternal separation paradigm. The above findings suggest that early\u2010life stress prior to neonatal hypoxia\u2010ischemia leads to significant alterations in synaptic plasticity of the dorsal hippocampus during adulthood, but does not exacerbate HI\u2010related changes in emotional behavior.<\/jats:p>","DOI":"10.1016\/j.ijdevneu.2016.04.002","type":"journal-article","created":{"date-parts":[[2016,5,8]],"date-time":"2016-05-08T11:45:41Z","timestamp":1462707941000},"page":"1-12","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Maternal separation prior to neonatal hypoxia\u2010ischemia: Impact on emotional aspects of behavior and markers of synaptic plasticity in hippocampus"],"prefix":"10.1002","volume":"52","author":[{"given":"Ioanna","family":"Markostamou","sequence":"first","affiliation":[{"name":"Laboratory of Cognitive Neuroscience School of Psychology Aristotle University of Thessaloniki Thessaloniki 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