Journal of Molecular Biology
Volume 426, Issue 20, 9 October 2014, Pages 3389-3412
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Review
Epigenetic Signaling in Psychiatric Disorders

https://doi.org/10.1016/j.jmb.2014.03.016Get rights and content

Highlights

  • Discussion of current evidence for epigenetic dysregulation in depression and addiction.

  • Insights from both animal and human studies.

  • Special focus on findings from developmental versus adult studies.

Abstract

Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function. While genetic factors are important in the etiology of disorders such as depression and addiction, relatively high rates of discordance among identical twins clearly indicate the importance of additional mechanisms. Environmental factors such as stress or prior drug exposure are known to play a role in the onset of these illnesses. Such exposure to environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental and adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression and addiction can be modeled in animals by inducing disease-like states through environmental manipulations (e.g., chronic stress, drug administration). Understanding how environmental factors recruit the epigenetic machinery in animal models reveals new insight into disease mechanisms in humans.

Graphical Abstract

Epigenetic mechanisms of gene regulation in hypothalamic-pituitary-adrenal axis (left) and reward (right) circuitry are modulated by stress and drug exposure and appear to underlie psychiatric disorders such as depression and addiction.

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Introduction

Psychiatric disorders impose an ever-increasing burden on society. Major depression and drug addiction are complex phenomena resulting from the interaction of several factors including neurobiological, genetic, cultural, and life experience. Both depression and addiction are characterized by functional and transcriptional alterations in several limbic brain regions implicated in regulating stress responses and reward [1], [2], [3], [4], [5]. Advances in the last decade have identified epigenetic mechanisms as important effectors in psychiatric conditions. Indeed, being at the foundation of gene regulation, epigenetic mechanisms are ideal candidates for the study of depression and addiction. Epigenetic mechanisms refer to the highly complex organization of DNA. This includes primarily many types of histone modifications [6] and nucleotide modifications such as DNA methylation [7] and hydroxymethylation [8]. More recently, non-coding RNAs such as microRNAs (miRNAs) have emerged as a related mechanism although not epigenetic per se. Mounting evidence has identified epigenetic regulation in the context of stress-induced depression and drug-induced addiction. These epigenetic alterations are site specific, largely in post-mitotic cells, and appear to be de novo rather than inherited. The majority of these findings come from animal models although interesting insights in humans are starting to accumulate.

Early development marks a time of rapid brain development and enhanced susceptibility to environmental insults. Epigenetic mechanisms of gene regulation are a particularly attractive explanation for how early-life exposures to stress or drugs exert life-long effects on neuropsychiatric phenomena. Developmental exposures to stress or drugs may have broader impact on epigenetic states and brain circuits than similar exposure later in life. Research to date has focused on relatively distinct neural circuits in exploring the consequences of developmental versus adult exposures.

The present review brings together findings relating to epigenetic mechanisms in depression and addiction from both adult and developmental studies and elaborates the potential offered by epigenetic analyses to better understand these complex disorders.

Section snippets

Epigenetics and Depression

Depression is a complex and heterogeneous disorder. Stressful life events represent a major factor in vulnerability to depression. However, the difficulty in defining specific subsets of depression has made clear identification of its multiple etiologies very difficult. Animal models offer a useful approach to study depression. Indeed, the development of chronic stress paradigms over the last decade, combined with the ability to objectively measure anhedonia and stress susceptibility in

Epigenetics and Addiction

In rodents, addiction-relevant transcriptional regulation is studied by exposing animals to drugs of abuse. Most commonly, this is experimenter-administered drug exposure, and it should be noted that although many effects are recapitulated in self-administration models, clearly some mechanisms are distinct. More work is needed to examine the generalizability of epigenetic mechanisms revealed by passive drug exposure paradigms to more rigorous drug self-administration models. The following

Limitations, Future Directions, and Concluding Remarks

A wealth of data from animal models and evolving evidence from postmortem human samples have established the important role of a diverse array of epigenetic regulatory mechanisms in mediating the transcriptional abnormalities that underlie depression and addiction. The studies in depression and addiction discussed here illustrate approaches that are being used to understand other psychiatric and neurodevelopmental disorders, including schizophrenia, bipolar disorder, autism spectrum disorders,

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    C.J.P., R.C.B., and B.L. contributed equally to this work.

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