Effect of environmental enrichment on resilience to chronic unpredictable stress: epigenetic regulation of the BDNF gene and consequences on ethanol consumption

Abstract

Environmental conditions exert a great influence on the behavioral and neurochemical effects induced by drugs of abuse. Stress plays an important role in the development of dependence, as well as in relapse. On the other hand, the exposure of rodents to stimuli such as toys, exercise wheels and fellowship with other individuals, a model known as environmental enrichment (EA), is capable of producing beneficial effects to the individual and preventing or reversing pathological conditions, including behavioral/neurochemical effects induced by drugs of abuse. Data from our laboratory demonstrated that EA decreased alcohol consumption in animals exposed to acute constraint stress (Marianno et al., 2017) and decreased the anxiogenic effect induced by acute stress, mediated by a reduction in the nuclear translocation of glucocorticoid (Novaes et al., 2017). In our previous study, we showed that EA prevented and reversed the development of behavioral sensitization to ethanol (Rueda et al., 2012) and decreased the concentrations of BDNF (Brain-Derived Neurotrophic Factor) in the prefrontal cortex of animals submitted to EA, suggesting a possible role of this neurotrophic factor in the neurochemical mechanisms induced by EA (Rueda et al., 2012). In addition, we also find alterations in the expression of microRNAs that are controlled by neurotrophic factors, such as BDNF, in animals that did not express behavioral sensitization to ethanol after EA exposure (Rueda, 2017). Several molecules are commonly involved in the signaling of dependence and stress induced neuroadaptation, such as corticotrophin releasing factor (CRF) and BDNF. Relapses due to emotional states and stress play an important role in the motivation to maintain alcohol consumption, as stress axis deregulation strengthens the search for the drug. The mechanisms by which AD induces its effects on stress resilience and to dependence are not elucidated.Several environmental stimuli lead to epigenetic control of Bdnf expression. Variations in BDNF concentrations occurring between individuals in response to a stimulus or pharmacological treatment may result not only from genetic polymorphism but also from altered epigenetic programming. This project aims to demonstrate the involvement of AD in the stress resilience promoted by AD and the role of epigenetic modifications in the BDNF gene in the prefrontal cortex; besides evaluating the HPA axis participation in this process, through the expression of the nuclear and cytosolic glucocorticoid receptor and inhibition of the HPA axis. The second part of the project aims to study the effects of EA on ethanol consumption in animals submitted to chronic unpredictable stress. (AU)