Abstract
Objective: To study the expression and DNA methylation of the Glial cell line-derived neurotrophic factor (GDNF) gene in the development of depression-like behaviors in rats experiencing maternal deprivation stress in early life.Methods: Newborn SD rats were randomly assigned to a normal control group (NOR) or maternal deprivation group (MD). An open field test (OPT), sucrose preference test (SPT), and a forced swimming test (FST) were used to evaluate rats' behaviors. Protein, mRNA, and methylation levels were measured by ELISA/Western blot, real-time PCR, and BiSulfte Amplicon sequencing PCR, respectively.Results: MD rats had significantly shorter total distance and more fecal pellets in OPT, a lower sucrose preference rate in SPT, and a longer immobility time in FST than NOR rats. Compared with NOR rats, MD rats showed a significantly higher plasma corticosterone (CORT) level. The levels of plasma dopamine (DA) and the GDNF were significantly lower in the MD rats than in NOR rats. In the ventral tegmental area (VTA) tissues, MD rats had a significantly higher level of methylation at the GDNF gene promoter than NOR rats. The expression of the GDNF mRNA and protein were significantly lower in MD rats than in NOR rats. The total distance was significantly correlated with plasma DA and GDNF, the DNA methylation level at the GDNF promoter and the GDNF mRNA level in the VTA. Fecal pellets showed a significant correlation with plasma CORT. The sucrose preference rate was significantly correlated with plasma DA, the DNA methylation level at the GDNF promoter and the GDNF mRNA level in the VTA. Immobility time showed a significant correlation with the plasma DA, the plasma GDNF and the GDNF mRNA level in the VTA.Conclusion: up-regulation of DNA methylation at the GDNF gene promotor and the subsequent down-regulation of the GDNF gene expression in the VTA, may be involved in the development of depression-like behaviors in rats experiencing MD in early life.
Highlights
Major depressive disorder (MDD) is a common psychiatric disorder with a lifetime prevalence of 3–17% [1]
Dopamine is most abundant in the central nervous system (CNS) and the body of dopaminergic neurons is mainly located in the ventral tegmental area (VTA) and projected to almost the entire brain [4], involved in the regulation of cognition, motivation, reward, reinforcement behavior, and emotions [5,6,7]
Our findings suggest that early life maternal deprivation has a long-term effect on rodent behaviors and induce depressivelike behaviors in adult rats
Summary
Major depressive disorder (MDD) is a common psychiatric disorder with a lifetime prevalence of 3–17% [1]. Previous studies on the etiology, suggest that MDD is multifactorial and involves both genetic and environmental factors. The effect of early life adversity on depression is poorly understood, the influences of both the genetic and environmental factors. The monoamine hypothesis proposes that MDD may be caused by the dysregulation of monoaminergic neurotransmitters in the central nervous system (CNS) including serotonin, dopamine (DA), and norepinephrine. Numerous studies have observed the deficiency of the dopaminergic system in patients with MDD [8,9,10]. Early life adversity influences the development of the dopaminergic system, followed by an impairment of its structures and functions [11,12,13]
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