From early-life fluoxetine exposure to lifelong, sex-specific behavioral changes: decoding the dynamics of sensitive periods

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Early-life experiences shape neural networks, with heightened plasticity during the so-called "sensitive periods" (SP). SP are regulated by the maturation of GABAergic parvalbumin-positive (PV+) interneurons, which become enwrapped by perineuronal nets (PNNs) over time, modulating SP closure. Additionally, the opening and closing of SP are orchestrated by two distinct gene clusters known as "trigger" and "brake". Interestingly alterations in SP markers have been identified in neuropsychiatric disorders, suggesting they may play a role in the emergence of these pathological conditions. Here, we investigate, in rats, whether the behavioral phenotypes observed in adults exposed to fluoxetine (FLX) during gestation or breastfeeding (until postnatal day 21) are due to alterations in SP dynamics. In line with the pathological-like adult phenotypes observed, the molecular results reveal a clear sex difference with significant changes in the density of PV+, in the proportion of PV+ cells surrounded by PNNs, as well as in the expression of trigger and brake genes across the lifespan, in the prefrontal cortex and dorsal hippocampus. In particular, we observed the strongest effect in the dentate gyrus (DG) of the dorsal hippocampus, with an anticipation in prenatal-FLX males and a delay in postnatal-FLX females of SP opening. We suggest that the molecular targets herein described may represent useful biomarkers to identify people with potentially increased vulnerability and, accordingly, we can hypothesize that strategies (pharmacological or not) aimed at correcting these abnormalities may be useful in preventing the pathological manifestation.

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