Maternal Deprivation Increased Vulnerability to Depression in Adult Rats Through DRD2 Promoter Methylation in the Ventral Tegmental Area.

Zhenli Guo,Shansi Li,Xiongzhao Zhu,Jialing Wu,Yi Zhang

doi:10.3389/fpsyt.2022.827667

Abstract

ObjectiveEarly life adversity is a risk factor for depression in adulthood; however, the underlying mechanisms are not well understood. This study aims to investigate the effect of DNA methylation of DRD2 gene on early life stress–induced depression in adult rats.MethodsNewborn Sprague–Dawley rats were randomly assigned to four groups: maternal deprivation group (MD), chronic unpredictable stress (CUS) group, maternal deprivation plus chronic unpredictable stress (MD/CUS) group, and normal control group (NOR). Behaviors were measured by open field test (OFT), sucrose preference test (SPT), and Original Research Article forced swimming test (FST). Fecal CORT level was detected by ELISA. Bisulfite amplicon sequencing PCR was used to assess methylation levels of DRD2 promoter.ResultsCUS and MD/CUS rats had a significantly shorter total distance, longer immobility time, and higher CORT level, while MD and MD/CUS rats had a significantly lower percentage of central distance, more feces, lower rate of sucrose preference, and lower levels of DRD2 protein and mRNA in the VTA than NOR rats. CUS rats showed a significantly higher DRD2 mRNA and protein levels in the VTA than NOR rats. CUS, MD, and MD/CUS rats showed a significantly higher level of DRD2 promoter methylation than NOR rats. CORT level was significantly correlated with the sucrose preference rate in SPT, the immobility time in FST, the total distance, and the number of fecal pellets in OFT. DRD2 protein level was significantly correlated with the sucrose preference rate and the number of fecal pellets. DRD2 mRNA level was significantly correlated with the percentage of central distance and the number of fecal pellets in OFT. The level of DRD2 promoter methylation was significantly correlated with the sucrose preference rate, immobility time, total distance, the percentage of central distance, and the number of fecal pellets.ConclusionsEarly life MD increased vulnerability to stress-induced depressive-like behavior in adult rats. Enhanced DRD2 promoter methylation in the VTA may increase the susceptibility to depression.

Highlights

This study aims to investigate the effect of DNA methylation of DRD2 gene on early life stress–induced depression in adult rats
CORT level was significantly correlated with the sucrose preference rate in sucrose preference test (SPT), the immobility time in forced swimming test (FST), the total distance, and the number of fecal pellets in open field test (OFT)
DRD2 mRNA level was significantly correlated with the percentage of central distance and the number of fecal pellets in OFT

Summary

Introduction

Depressive disorder is one of the most prevalent psychiatric illnesses. Data from WHO demonstrated that the lifetime prevalence of depression is as high as 18.1% globally [1]. The childhood or early life period is sensitive to adverse events that increase the risk of depression [3, 4]. This predisposition, or vulnerability to depression is poorly understood. Previous studies show that DRD2 plays a key role on the development of stress-related depression [11]. The study of Chen et al [12] found that CUS induces depression-like behaviors and upregulates the expression of DRD2 in the prefrontal cortex of rats. Our previous study revealed that early life maternal deprivation (MD) induces aberrant expression of DRD2 gene in the mesocorticolimbic DA system of adult rats, especially elevates DRD2 gene expression in the striatum, and reduces DRD2 gene expression in the VTA [14–17]. The molecular mechanisms regulating DRD2 gene expression have yet to be fully understood

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Conclusion