• ArraesGreicy CoelhoGCNeuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Christus Uni, BarretoFrancisco StefânioFSNeuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Labora, VasconcelosGermana SilvaGSNeuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil., LimaCamila Nayane de CarvalhoCNCNeuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; T, da SilvaFrancisco Eliclécio RodriguesFERNeuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, B, RibeiroWesley Lyeverton CorreiaWLCDepartment of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil. Electronic address: wesley.ribeiro@ufc.br., de SousaFrancisca Cléa FlorençoFCFNeuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil., FurtadoCristiana Libardi MirandaCLMLaboratory of Experimental Oncology, Postgraduate Program in Translational Medicine, Drug Research and Development Center, Federal University of Ceara, Fortaleza, Ceará, Brazil; Graduate Program in Medical Sciences, Expe, and Danielle S Macêdo.
• Neuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Christus University Center (Unichristus-CE), Fortaleza, CE, Brazil.
• Neuroscience. 2024 Jul 23; 551: 205216205-216.

AbstractHere, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.

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