RESUMO
Prenatal stress (PS) exposure is known to increase the risk of developing emotional disorders like major depression in later life. However, some individuals do not succumb to adversity following developmental stress exposure, a phenomenon referred to as resilience. To date, the molecular mechanisms explaining why some subjects are vulnerable and others more resilient to PS are far from understood. Recently, we have shown that the serotonin transporter (5-HTT) gene may play a modulating role in rendering individuals susceptible or resilient to PS. However, it is not clear which molecular players are mediating the interaction between PS and the 5-Htt genotype in the context of vulnerability and resilience to PS. For this purpose, we performed a microarray study with the help of Affymetrix GeneChip® Mouse Genome 430 2.0 Array, in which we separated wild-type and heterozygous 5-Htt-deficient (5-Htt+/-) PS offspring into susceptible and resilient offspring according to their performance in the forced swim test. Performance-oriented LIMMA analysis on the mRNA expression microarray data was followed by subsequent Spearman's correlation analysis linking the individual qRT-PCR mRNA expression data to various anxiety- and depression-related behavioral and neuroendocrine measures. Results indicate that, amongst others, Fos-induced growth factor (Figf), galanin receptor 3 (Galr3), growth hormone (Gh) and prolactin (Prl) were differentially expressed specifically in resilient offspring when compared to controls, and that the hippocampal expression of these genes showed several strong correlations with various measures of the hypothalamus-pituitary-adrenal axis (re)activity. In conclusion, there seems to be an intricate interplay between the expression of Figf, Galr3, Gh and Prl and neuroendocrine regulation, which may be critical in mediating resilience to PS exposure. More insight into the exact role of these molecular players may significantly enhance the development of new treatment strategies for stress-related emotional disorders.
Assuntos
Comportamento Animal/fisiologia , Cortisona/metabolismo , Predisposição Genética para Doença , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Estresse Psicológico/genética , Animais , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Hormônio do Crescimento/genética , Camundongos , Gravidez , Prolactina/genética , Receptor Tipo 3 de Galanina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/metabolismo , Fator D de Crescimento do Endotélio Vascular/genéticaRESUMO
Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-Htt×PS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety- and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip® Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotype×PS manner, indicating a gene×environment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice--particularly females--at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
