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

Abstract

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.

Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala

“…As discussed earlier, a moderating factor of MS in this regard might have been the maternal response to MS exposure (Own et al, 2013). The molecular basis of this phenomenon of less effect of adverse factors has been investigated in manifold experiments and a number of behavioral, physiological and molecular factors were identified as relevant mediators of individual susceptibility to stress (Jakob et al, 2014; Anacker et al, 2016; Han and Nestler, 2017). As one important factor of individual stress susceptibility epigenetic modifications such as DNA methylation have been identified (Dudley et al, 2011).…”

Impact of varying social experiences during life history on behaviour, gene expression, and vasopressin receptor gene methylation in mice

“…Elements known for their modulatory function of the HPA axis include the glucocorticoid receptor (GR; Nr3c1 ) 17 , 28 , corticotropin releasing hormone receptor 1 ( Crhr1 ) 29 , 30 , and brain-derived neurotrophic factor ( Bdnf ) 31 , 32 . Furthermore, growth hormone ( Gh ) and myelin basic protein ( Mbp ) appeared as candidate genes in previous studies 33 – 35 . Both play important roles in the brain as they are involved in neural processes such as myelination.…”

Active coping of prenatally stressed rats in the forced swimming test: involvement of theNurr1gene

“…In contrast, it has been reported that male PS Sprague-Dawley rats displayed vulnerability in the FST (van den Hove et al, 2013). Other studies performed with mice have also demonstrated contrasting behavioral, gender-specific responses in the FST as a result of prenatal stress (Jakob et al, 2014;van den Hove et al, 2011).…”