Abstract
BackgroundEarly-life stress can leave persistent epigenetic marks that may modulate vulnerability to psychiatric conditions later in life, including anxiety, depression and stress-related disorders. These are complex disorders with both environmental and genetic influences contributing to their etiology. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. Moreover, mutations in the MECP2 gene are the primary cause of Rett syndrome and, to a lesser extent, of a range of other major neurodevelopmental disorders. Here, we aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits.MethodsUsing Mecp2 heterozygous and wild-type female mice we investigated the effects of the interaction of Mecp2 haplodeficiency with maternal separation later in life, by assessing anxiety-related behaviors and measuring concomitant c-FOS expression in stress- and anxiety-related brain regions of adolescent females. Moreover, arginine vasopressin and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus were analyzed for neuronal activation.ResultsIn wild-type mice, maternal separation caused a reduction in anxiety-like behavior and in the activation of the hypothalamic paraventricular nucleus, specifically in corticotropin-releasing hormone-positive cells, after the elevated plus maze. This effect of maternal separation was not observed in Mecp2 heterozygous females that per se show decreased anxiety-like behavior and concomitant decreased paraventricular nuclei activation.ConclusionsOur data supports that MeCP2 is an essential component of HPA axis reprogramming and underlies the differential response to anxiogenic situations later in life.
Highlights
Early-life stress (ELS) constitutes a major risk factor for the development of psychiatric disorders, including anxiety disorders
Experimental subjects were submitted to tests starting with the elevated plus maze (EPM), open field (OF), forced swimming test (FST), and finishing with a second EPM performed in bright light conditions, 1 h after which animals were sacrificed to assess FOS proto-oncogene (c-FOS) activation patterns
maternal separation (MS) renders female mice more resilient to anxiety‐ and depressive‐like behaviors, an effect recapitulated by Methyl-CpG Binding Protein 2 (MeCP2) deficiency Elevated plus maze Animals were first tested in the EPM in a single 5-min session
Summary
Early-life stress (ELS) constitutes a major risk factor for the development of psychiatric disorders, including anxiety disorders. MeCP2 has been attributed a key role in the Abellán‐Álvaro et al Journal of Neurodevelopmental Disorders (2021) 13:59 control of neuronal activity-dependent gene expression [4, 5] and in experience-dependent epigenetic programming [6, 7]. Adverse events occurring during this period are engraved in ‘permanent’ epigenetic marks, with MeCP2 being a master regulator of these processes [6] This way, early life adversity will have an impact in the stress response later in life, when individuals are faced with a stressor [9]. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. We aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits
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