Abstract
Psychiatric disorders entail maladaptive processes impairing individuals’ ability to appropriately interface with environment. Among them, depression is characterized by diverse debilitating symptoms including hopelessness and anhedonia, dramatically impacting the propensity to live a social and active life and seriously affecting working capability. Relevantly, besides genetic predisposition, foremost risk factors are stress-related, such as experiencing chronic psychosocial stress—including bullying, mobbing and abuse—, and undergoing economic crisis or chronic illnesses. In the last few years the field of epigenetics promised to understand core mechanisms of gene-environment crosstalk, contributing to get into pathogenic processes of many disorders highly influenced by stressful life conditions. However, still very little is known about mechanisms that tune gene expression to adapt to the external milieu. In this Perspective article, we discuss a set of protective, functionally convergent epigenetic processes induced by acute stress in the rodent hippocampus and devoted to the negative modulation of stress-induced immediate early genes (IEGs) transcription, hindering stress-driven morphostructural modifications of corticolimbic circuitry. We also suggest that chronic stress damaging protective epigenetic mechanisms, could bias the functional trajectory of stress-induced neuronal morphostructural modification from adaptive to maladaptive, contributing to the onset of depression in vulnerable individuals. A better understanding of the epigenetic response to stress will be pivotal to new avenues of therapeutic intervention to treat depression, especially in light of limited efficacy of available antidepressant drugs.
Highlights
Molecular psychiatry mainly recognizes three typologies of stressful events, namely positive stress, tolerable stress and toxic stress (McEwen, 2017). ‘‘Positive’’ stress entails reward-associated paradigms including whatever hard paths to meet our life expectations
Given that stress is highly effective in increasing the level of anxiety, the research group proposed that LysineSpecific Demethylase 1 (LSD1) mediated occlusion of stress-induced immediate early genes (IEGs) transcription, must represent a secondary epigenetic response with adaptive meaning aimed at buffering excessive consolidation of stress plasticity in terms of anxiety (Rusconi et al, 2016, 2017)
We retrieved and conceptually linked from the literature a set of epigenetic modifications occurring to control stress-induced transcription, representing novel examples of homeostatic processes elicited in rodent models by different environmental stressful events
Summary
Molecular psychiatry mainly recognizes three typologies of stressful events, namely positive stress, tolerable stress and toxic stress (McEwen, 2017). ‘‘Positive’’ stress ( known as eustress; Selye, 1998) entails reward-associated paradigms including whatever hard paths to meet our life expectations (job promotions and achievements in general). Foot shock paradigm induces in the hippocampus of stressed animals IEGs transcription as primary response, which is supported by increased levels of the euchromatin-associated histone mark H3K4me3 at the level of the IEG egr1 (Gupta et al, 2010).
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