Abstract
DNA methylation and gene expression can be altered by early life stress (ELS) and/or ethanol consumption. The present study aimed to investigate whether DNA methylation of the Vesicular Glutamate Transporters (Vglut)1-3 is related to previously observed Vglut1-3 transcriptional differences in the ventral tegmental area (VTA), nucleus accumbens (Acb), dorsal striatum (dStr) and medial prefrontal cortex (mPFC) of adult rats exposed to ELS, modelled by maternal separation, and voluntary ethanol consumption. Targeted next-generation bisulfite sequencing was performed to identify the methylation levels on 61 5′-cytosine-phosphate-guanosine-3′ sites (CpGs) in potential regulatory regions of Vglut1, 53 for Vglut2, and 51 for Vglut3. In the VTA, ELS in ethanol-drinking rats was associated with Vglut1-2 CpG-specific hypomethylation, whereas bidirectional Vglut2 methylation differences at single CpGs were associated with ELS alone. Exposure to both ELS and ethanol, in the Acb, was associated with lower promoter and higher intronic Vglut3 methylation; and in the dStr, with higher and lower methylation in 26% and 43% of the analyzed Vglut1 CpGs, respectively. In the mPFC, lower Vglut2 methylation was observed upon exposure to ELS or ethanol. The present findings suggest Vglut1-3 CpG-specific methylation signatures of ELS and ethanol drinking, underlying previously reported Vglut1-3 transcriptional differences in the mesocorticolimbic brain.
Highlights
Adversity during early life has been linked to psychopathology later in life, including alcohol use disorder (AUD)[1,2,3]
Correlations between cytosine-phosphate-guanosine-3′ sites (CpGs)-methylation and ethanol intake during PNW15 and PNW16 and their directions were similar for the vast majority of CpGs for MS15E, MS360E and MS360E low drinkers, but not for MS360E moderate and high drinkers (Table S10b, c)
Vesicular Glutamate Transporters (Vglut) methylation varied in a gene- or brain region-dependent way, in the groups previously found to differ in their Vglut mRNA expression levels[30], whereas there was not a pattern of association between these effects and the gene targeted regulatory region
Summary
Adversity during early life has been linked to psychopathology later in life, including alcohol use disorder (AUD)[1,2,3]. Early life stress (ELS) can lead to epigenetic modifications, such as alterations in DNA methylation patterns, which can in turn affect gene expression[4]. Differences in maternal care in rats and humans have been associated with altered HPA-axis response to stress and negative mental health via differential methylation of the promoter of the glucocorticoid receptors[7,8]. Altered glutamatergic neurotransmission has been implicated in various phases of the addiction cycle, from initial and voluntary to chronic and compulsory alcohol u se[13,14]. This is not of surprise considering that glutamate is the primary excitatory neurotransmitter in the brain[15]. ELS has been shown to result in increased excitatory glutamatergic neurotransmission in the paraventricular nucleus of the h ypothalamus[19], and in disturbed homeostasis of glutamatergic s ynapses[20], as well as in aberrant reward processing and drug-seeking behaviors, likely mediated by disturbances in dopaminergic and glutamatergic neurotransmission in the PFC and the Acb[21]
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