Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene × Environment Interactions

Hove, Daniël L.A. van den; Jakob, Sissi Brigitte; Schraut, Karla‐Gerlinde; Kenis, Günter; Schmitt, Angelika; Kneitz, Susanne; Scholz, Claus‐Jürgen; Wiescholleck, Valentina; Ortega, Guillermo J.; Prickaerts, Jos; Steinbusch, Harry W.M.; Lesch, Klaus‐Peter

doi:10.1371/journal.pone.0022715

Cited by 75 publications

(111 citation statements)

References 91 publications

(95 reference statements)

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“…For this particular study, only brain tissue of female PS offspring was used. As shown before by our group [20,22], when using this particular prenatal restraint stress paradigm, predominantly female offspring seem to be vulnerable to the effects of PS. Moreover, regarding the animals used in the present study, when stratifying for sex, the PS effect as observed in the FST was only significant for females (F 3, 35 = 0.980, p = 0.329 vs. F 3, 32 = 5.494, p = 0.025, for males and females, respectively).…”

Section: Methodssupporting

confidence: 66%

“…When the offspring reached the age of 2 months (P60), behavioral experiments were started (n = 10-14/group), as reported in detail previously [22]. Briefly, first, memory abilities were assessed using the object recognition task, after which anxiety- and depressive-like behavior were tested using the elevated zero maze test and FST, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the adrenals were removed. Adrenal weight was recorded and results were shown in our earlier publication [22]. An overview of the main behavioral and physiological effects is depicted in online supplementary table 1 (for all online suppl.…”

Section: Methodsmentioning

confidence: 99%

“…As described in detail previously [22], the left half of the hippocampus was homogenized using 500 µl of PegGOLD RNAPure (Peglab, Erlangen, Germany) and metal beads (3 min, 20 Hz in a TissueLyser; Qiagen, Hilden,Germany). Afterwards, 100 µl of chloroform was added and samples were centrifuged for 5 min (4°C, 12.000 g ).…”

Section: Methodsmentioning

confidence: 99%

“…More specifically, the performance-based LIMMA analysis offers the opportunity to identify molecular mechanisms specific to either vulnerability or resilience to PS. In doing so, WT and 5-Htt+/- mice were examined separately, since the 5-Htt+/- genotype is known to render the offspring more vulnerable to PS per se [22]. The level of statistical significance was assumed to exist at p < 0.05 in all tests.…”

Section: Methodsmentioning

confidence: 99%

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Differential Effects of Prenatal Stress in Female 5-Htt-Deficient Mice: Towards Molecular Mechanisms of Resilience

Jakob

Schraut²,

Schmitt³

et al. 2014

Dev Neurosci

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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.

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Section: Methodssupporting

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Differential Effects of Prenatal Stress in Female 5-Htt-Deficient Mice: Towards Molecular Mechanisms of Resilience

Jakob

Schraut²,

Schmitt³

et al. 2014

Dev Neurosci

Self Cite

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Animal Models of Developmental Psychopathology

Howell

Neigh

Sánchez

2016

Developmental Psychopathology

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In the last decade much progress has been made in research using animal models of developmental psychopathology. The field has moved from the demonstration of long‐term impacts of early adversity on behavioral and physiological development and the role of genetic risks for vulnerability, to including transgenerational transmission of stress‐induced phenotypes through epigenetic modifications. Additional and critical paradigm shifts have also taken place, including increased focus on ecologically and ethologically valid animal models, research on resilience, the adolescent transition as a period of brain and behavioral reorganization, and sex differences. In this chapter we review recent literature using rodent and nonhuman primate animal models that examines the biological mechanisms through which the early environment programs neurobehavioral, cognitive, and physiological development. We discuss the evolutionary role of this plasticity on behavioral development, as it has an adaptive value in changing environments. Because of maternal care's critical role in early environment, we focus on models that study the effects of mother–infant relationship disruption and dissect the mechanisms by which maternal care regulates the development of brain circuits that control emotional and social behaviors of relevance for developmental psychopathology. Finally, we discuss developmental sensitive/critical periods as windows of opportunity for plastic adaptation of developing organisms to the environment that, if taken too far—as in the case of early traumatic experiences such as childhood maltreatment—lead to maladaptive developmental trajectories (psychopathology, pathophysiology). Animal models of early life adversity are paramount to understand the basic mechanisms and principles that translate early experience into developmental outcomes in our own species.

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Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress

et al. 2016

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Stress exposure during gestation is implicated in several neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous research showed that prenatal stress increases risk for ASD with peak exposure during the end of the second and the beginning of the third trimester. However, exposures to prenatal stress do not always result in ASD, suggesting that other factors may interact with environmental stressors to increase ASD risk. The present study examined a maternal genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR) affecting stress tolerance and its interaction with the effect of environmental stressors on risk for ASD. Two independent cohorts of mothers of ASD children recruited by the University of Missouri and Queen's University were surveyed regarding the prenatal environment and genotyping on 5-HTTLPR was performed to explore this relationship. In both samples, mothers of children with ASD carrying the stress susceptible short allele variant of 5-HTTLPR experienced a greater number of stressors and greater stress severity when compared to mothers carrying the long allele variant. The temporal peak of stressors during gestation in these mothers was consistent with previous findings. Additionally, increased exposure to prenatal stress was not reported in the pregnancies of typically developing siblings from the same mothers, regardless of maternal genotype, suggesting against the possibility that the short allele might increase the recall of stress during pregnancy. The present study provides further evidence of a specific maternal polymorphism that may affect the risk for ASD with exposure to prenatal stress. Autism Res 2016, 9: 1151-1160. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

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Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene × Environment Interactions

Cited by 75 publications

References 91 publications

Differential Effects of Prenatal Stress in Female 5-Htt-Deficient Mice: Towards Molecular Mechanisms of Resilience

Differential Effects of Prenatal Stress in Female 5-Htt-Deficient Mice: Towards Molecular Mechanisms of Resilience

Animal Models of Developmental Psychopathology

Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress

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