Prenatally traumatized mice reveal hippocampal methylation and expression changes of the stress-related genes Crhr1 and Fkbp5

Anne-Christine Plank,Stefan Frey,Fabio Canneva,Stephan Von Hörsten,Oliver Kratz,Gunther H Moll,Lukas Andreas Basedow,Jalal Solati,Yulia Golub

doi:10.1038/s41398-021-01293-y

Anne-Christine Plank, Stefan Frey + Show 7 more

Open Access

https://doi.org/10.1038/s41398-021-01293-y

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Abstract

In our previous study, we found that prenatal trauma exposure leads to an anxiety phenotype in mouse pups, characterized by increased corticosterone levels and increased anxiety-like behavior. In order to understand the mechanisms by which aversive in utero experience leads to these long-lasting behavioral and neuroendocrine changes, we investigated stress reactivity of prenatally traumatized (PT) mice, as well as the expression and methylation levels of several key regulatory genes of the stress axis in the dorsal hippocampus (dHPC) of the PT embryo and adult mice. We detected increased corticotropin-releasing hormone receptor 1 (Crhr1) and decreased FK506 binding protein 5 (Fkbp5) mRNA levels in the left dHPC of adult PT mice. These alterations were accompanied by a decreased methylation status of the Crhr1 promoter and an increased methylation status of the Fkbp5 promoter, respectively. Interestingly, the changes in Fkbp5 and Crhr1 mRNA levels were not detected in the embryonic dHPC of PT mice. Together, our findings provide evidence that prenatal trauma has a long-term impact on stress axis function and anxiety phenotype associated with altered Crhr1 and Fkbp5 transcripts and promoter methylation.

Highlights

The developmental triad of growth, maturation, and learning is known to be modulated by an individuals early environment[1]
maternal trauma (MT)/prenatally traumatized (PT) affects basal and stress-induced CORT secretion CORT measurements in dams 7 days before and 60 min after mild stress exposure revealed a significant effect of MT (F1,23 = 5.389, p = 0.03) and of stress exposure (F1,23 = 363.5, p < 0.0001), with increased CORT levels after mild stress exposure and elevated CORT levels in MT as compared to no MT mice (Fig. 2A)
In order to study the mechanism of HPA axis changes following prenatal trauma exposure and being raised by a traumatized mother, we measured the expression and methylation changes of the HPA axis key genes Crhr[1], Nr3c1, Nr3c2, and Fkbp[5] in the left and right dorsal hippocampus (dHPC) of PT and no PT mice on postnatal day (PND) 150

Summary

Introduction

The developmental triad of growth, maturation, and learning is known to be modulated by an individuals early environment[1]. Early life experiences, including exposure to the maternal environment, set the growth trajectory of the child and are recognized as a key factor for disease susceptibility later in life[2]. When there is a mismatch between early and later life environment, these changes — originally intended to be “beneficial” — all together or in parts suddenly become maladaptive[5]. Such specific and often traumaassociated maladaptation increases an individual’s disease susceptibility[4,5]. Children of mothers who experienced a traumatic event during pregnancy are at higher risk to develop a psychiatric disorder later in life[6,7,8]

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