Enriquecimento ambiental como estratégia de prevenção na esquizofrenia: evidências comportamentais e neuroquímicas de camundongos submetidos a modelo de desafio imune neonatal

Abstract

Schizophrenia is a complex mental disorder of variable phenotypic expression and multifactorial etiology still poorly understood characterized by symptoms such as psychosis, hallucinations, delusions and abnormal thoughts. Patients with this disorder develop with declining functional potential, leading to social and occupational disability in more than 50% of cases. Currently, early treatment is essential in preventing complications of chronification, although there are no prevention strategies for the development of this mental disorder. There is a strong association between exposure to environmental factors, such as perinatal infections during critical periods of neurodevelopment, with the development of schizophrenia in adulthood. In addition, positive environmental influences (eg, controlled environment) or negative influences (eg, cannabis sativa use) in adolescence may protect or potentiate, respectively, the risk for the development of schizophrenia. In this context, the objective of this study was to study the preventive effect of the non-pharmacological strategy, environmental enrichment (EA), which represents the mice Swiss exposure to an aggregate environment of stimulation resources in mice submitted to the model of schizophrenia by "2Hits”, which consists of exposure to immune challenge in the neonatal period combined with unpredictable stress in adolescence, two important risk factors for schizophrenia. The behavioral evaluations were performed through the pre-pulse Inhibition (IPP) and open field tests, for evaluation of positive symptoms, Y-labyrinth, for evaluation of working memory and social interaction, to determine social behavior. Parameters related to the hypothesis of schizophrenia, such as neuroinflammatory (through the determination of microglial activation), glutamatergic (by the expression of the NMDA receptor NR2b subunit), serotonergic (through the methylation of the do gene Slc6a4 serotonin transporter), and neurogenesis, through the expression of doublecortin (DCX). The animals submitted to prevention with AD presented better cognitive performance, better startle response, were more explorers, tending to be less anxious and preserving the social interaction capacity when compared to the schizophrenia group. Prevention by AE reduced microglial activation without altering the NR2b subunit in relation to the schizophrenia group. Neurogenesis was observed in animals submitted to AS prevention. Prevention by AD caused hypomethylation of the Slc6a4 gene evaluated by High Resolution Melting (HRM), while the schizophrenia group presented approximately 50% methylation. It is concluded that an enriched environment may be an important strategy to prevent schizophrenia, by mechanisms involving anti-inflammatory effect, neurogenesis and alterations in the methylation of the gene Slc6a4.