scholarly journals DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early-life stress and adult ethanol exposure—an explorative study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Vrettou ◽  
Liying Yan ◽  
Kent W. Nilsson ◽  
Åsa Wallén-Mackenzie ◽  
Ingrid Nylander ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Glutamate Transporters ◽  
Ethanol Consumption ◽  
Ethanol Exposure ◽  
Ethanol Drinking ◽  
Vesicular Glutamate Transporters

AbstractDNA 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.

scholarly journals DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early life stress and ethanol exposure in adulthood

2021 ◽  
Author(s):  
Maria Vrettou ◽  
Liying Yan ◽  
Kent Nilsson ◽  
Åsa Wallén-Mackenzie ◽  
Ingrid Nylander ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Glutamate Transporters ◽  
Ethanol Consumption ◽  
Ethanol Exposure ◽  
Ethanol Drinking ◽  
Vesicular Glutamate Transporters

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 ELS- or ethanol-only. 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.

scholarly journals Altered hypothalamic DNA methylation and stress-induced hyperactivity following early life stress

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Eamon Fitzgerald ◽  
Matthew C. Sinton ◽  
Sara Wernig-Zorc ◽  
Nicholas M. Morton ◽  
Megan C. Holmes ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Open Field ◽  
Stress Responses ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Neonatal Period ◽  
Early Life Stress ◽  
Mediated Effects

AbstractExposure to early life stress (ELS) during childhood or prenatally increases the risk of future psychiatric disorders. The effect of stress exposure during the neonatal period is less well understood. In preterm infants, exposure to invasive procedures is associated with altered brain development and future stress responses suggesting that the neonatal period could be a key time for the programming of mental health. Previous studies suggest that ELS affects the hypothalamic epigenome, making it a good candidate to mediate these effects. In this study, we used a mouse model of early life stress (modified maternal separation; MMS). We hypothesised MMS would affect the hypothalamic transcriptome and DNA methylome, and impact on adult behaviour. MMS involved repeated stimulation of pups for 1.5 h/day, whilst separated from their mother, from postnatal day (P) 4–6. 3’mRNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing were performed on hypothalamic tissue at P6. Behaviour was assessed with the elevated plus, open field mazes and in-cage monitoring at 3–4 months of age. MMS was only associated with subtle changes in gene expression, but there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. ELS has marked effects on DNA methylation in the hypothalamus in early life and results in stress-specific hyperactivity in young adulthood. These results have implications for the understanding of ELS-mediated effects on brain development.

scholarly journals Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Thabisile Mpofana ◽  
Willie M. U. Daniels ◽  
Musa V. Mabandla
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Neurotrophic Factor ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Corticosterone Concentration ◽  
Factor Gene ◽  
Gdnf Gene

Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA), we measured corticosterone (CORT) in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life.

scholarly journals Epigenetic Impacts of Early Life Stress in Fetal Alcohol Spectrum Disorders Shape the Neurodevelopmental Continuum

2021 ◽  
Vol 14 ◽  
Author(s):  
Bonnie Alberry ◽  
Benjamin I. Laufer ◽  
Eric Chater-Diehl ◽  
Shiva M. Singh
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Fetal Alcohol Spectrum Disorders ◽  
Early Life Stress ◽  
Ethanol Exposure ◽  
Prenatal Ethanol Exposure ◽  
Fetal Alcohol ◽  
Spectrum Disorders ◽  
Fetal Alcohol Spectrum

Neurodevelopment in humans is a long, elaborate, and highly coordinated process involving three trimesters of prenatal development followed by decades of postnatal development and maturation. Throughout this period, the brain is highly sensitive and responsive to the external environment, which may provide a range of inputs leading to positive or negative outcomes. Fetal alcohol spectrum disorders (FASD) result from prenatal alcohol exposure (PAE). Although the molecular mechanisms of FASD are not fully characterized, they involve alterations to the regulation of gene expression via epigenetic marks. As in the prenatal stages, the postnatal period of neurodevelopment is also sensitive to environmental inputs. Often this sensitivity is reflected in children facing adverse conditions, such as maternal separation. This exposure to early life stress (ELS) is implicated in the manifestation of various behavioral abnormalities. Most FASD research has focused exclusively on the effect of prenatal ethanol exposure in isolation. Here, we review the research into the effect of prenatal ethanol exposure and ELS, with a focus on the continuum of epigenomic and transcriptomic alterations. Interestingly, a select few experiments have assessed the cumulative effect of prenatal alcohol and postnatal maternal separation stress. Regulatory regions of different sets of genes are affected by both treatments independently, and a unique set of genes are affected by the combination of treatments. Notably, epigenetic and gene expression changes converge at the clustered protocadherin locus and oxidative stress pathway. Functional studies using epigenetic editing may elucidate individual contributions of regulatory regions for hub genes and further profiling efforts may lead to the development of non-invasive methods to identify children at risk. Taken together, the results favor the potential to improve neurodevelopmental outcomes by epigenetic management of children born with FASD using favorable postnatal conditions with or without therapeutic interventions.

scholarly journals P-03ETHANOL AFFECTS LIMBIC AND STRIATAL EXPRESSION OF VESICULAR GLUTAMATE TRANSPORTERS IN OUTBRED RATS EXPOSED TO EARLY LIFE STRESS

2015 ◽  
Vol 50 (suppl 1) ◽  
pp. i45.3-i45
Author(s):  
M. Vrettou ◽  
L. Granholm ◽  
A. Todkar ◽  
K. W. Nilsson ◽  
Å. Wallén-Mackenzie ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Glutamate Transporters ◽  
Vesicular Glutamate Transporters

scholarly journals Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

2020 ◽  
Author(s):  
Eamon Fitzgerald ◽  
Matthew C Sinton ◽  
Sara Wernig-Zorc ◽  
Nicholas M Morton ◽  
Megan C Holmes ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Preterm Birth ◽  
Psychiatric Disorders ◽  
Open Field ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Mediated Effects ◽  
Novel Model

AbstractEarly life stress during childhood is associated with a number of psychiatric disorders that manifest across the life course. Preterm birth is a profound stressor, and an important cause of cognitive impairment, as well as neurodevelopmental and psychiatric disorders. However, the mechanisms that link events during the early neonatal period with later functional problems are poorly understood. We developed a novel mouse model of early life stress (modified maternal separation; MMS) with specific relevance to preterm birth (PTB) and hypothesised it would affect the hypothalamic transcriptome and DNA methylome and impact on behaviour in adulthood. MMS consisted of repeatedly stimulating pups for 1.5 hours/day, whilst separated from their mother, from postnatal day (P)4-6. 3’ RNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing was performed on the hypothalamus at P6. Behaviour was assessed with the elevated plus and open field mazes, and in-cage monitoring at 3-4 months of age. Although MMS was only associated with subtle changes in gene expression there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS also resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. In conclusion we describe a novel model of early life stress with relevance to PTB, with marked effects on DNA methylation in the hypothalamus and with stress-specific hyperactivity in young adulthood. We suggest that these results have implications for the understanding of early life stress mediated effects on brain development.

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