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Involvement of epigenetic mechanisms induced by DNA methylation on stress-induced behavioral consequences and on the expression of genes involved in the neurobiology of depression


Recent studies indicate that epigenetic mechanisms migh be involved in the neurobiology of depression. For example, DNA methylation, which is associated with transcriptional repression, is increased by exposure to stress. Besides, high levels of methylation in specific gene loci were found in the brains of suicide victims. In addition, preliminary results of our research group showed that systemic administration of inhibitors of DNA methylation induces antidepressant-like effect in the forced swimming test. However, the molecular mechanisms and brain structures involved in these effects, as well as the pharmacological profile induced by these treatments, have not been investigated yet. Moreover, the effects induced by these treatments in animals exposed to other animal models predictive of antidepressant effects remains to be investigated.Therefore, this project aims to continue the investigation about the involvement of DNA methylation in the development of behavioral consequences induced by stress by studying the effects induced by other inhibitors of DNA methylation, as well as the molecular mechanisms involved in these effects. To do so, it will be tested the effects induced by acute and subchronic administration of nucleoside (5-aza-2-deoxiitidina) and non-nucleoside (RG-108) inhibitors of DNA methylation on the behavior of animals submitted to different models that involve presentation of stress (forced swimming, footshocks, restraint). In addition, we intend to evaluate the pattern of DNA methylation in candidate genes in structures involved in depression patophisyiology (hippocampus, prefrontal cortex and striatum) in response to treatment with DNA methylation inhibitors or with antidepressant drugs, in stressed and non stressed animals. (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PEREIRA, VITOR S.; CASAROTTO, PLINIO C.; HIROAKI-SATO, VINICIUS A.; SARTIM, ARIANDRA G.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.. Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: Involvement of nitric oxide. European Neuropsychopharmacology, v. 23, n. 12, p. 1769-1778, . (11/17281-7, 07/03685-3)
SCOPINHO, AMERICA A.; LISBOA, SABRINA F. S.; GUIMARAES, FRANCISCO S.; CORREA, FERNANDO M. A.; RESSTEL, LEONARDO B. M.; JOCA, SAMIA R. L.. Dorsal and Ventral Hippocampus Modulate Autonomic Responses but Not Behavioral Consequences Associated to Acute Restraint Stress in Rats. PLoS One, v. 8, n. 10, . (11/17281-7, 12/09300-4)
SALES, AMANDA J.; MACIEL, IZAQUE S.; SUAVINHA, ANGELICA C. D. R.; JOCA, SAMIA R. L.. Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects. Molecular Neurobiology, v. 58, n. 2, p. 777-794, . (12/17626-7, 15/01955-0, 11/17281-7)
SALES, AMANDA J.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.. CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim. Behavioural Brain Research, v. 388, . (12/17626-7, 11/17281-7)
SALES, AMANDA JULIANA; LOURENCO JOCA, SAMIA REGIANE. Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels. ACTA NEUROPSYCHIATRICA, v. 28, n. 1, p. 11-22, . (12/17626-7, 11/17281-7)

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