The link between parental psychological control, depressive symptoms and epigenetic changes in the glucocorticoid receptor gene (NR3C1)

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Although the association between maternal depression and adverse child outcomes is well established, the strength of the association, the breadth or specificity of the outcomes, and the role of moderators are not known. This information is essential to inform not only models of risk but also the design of preventive interventions by helping to identify subgroups at greater risk than others and to elucidate potential mechanisms as targets of interventions. A meta-analysis of 193 studies was conducted to examine the strength of the association between mothers' depression and children's behavioral problems or emotional functioning. Maternal depression was significantly related to higher levels of internalizing, externalizing, and general psychopathology and negative affect/behavior and to lower levels of positive affect/behavior, with all associations small in magnitude. These associations were significantly moderated by theoretically and methodologically relevant variables, with patterns of moderation found to vary somewhat with each child outcome. Results are interpreted in terms of implications for theoretical models that move beyond main effects models in order to more accurately identify which children of depressed mothers are more or less at risk for specific outcomes.

Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.