| 1. |
- Bendre, Megha, et al.
(författare)
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Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
- 2019
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Ingår i: Alcohol. - : Elsevier BV. - 0741-8329 .- 1873-6823. ; 79, s. 7-16
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Tidskriftsartikel (refereegranskat)abstract
- Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.
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| 2. |
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| 3. |
- Comasco, Erika, 1982-, et al.
(författare)
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Constitutive serotonin transporter reduction resembles maternal separation with regard to stress-related gene expression
- 2019
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 10:7, s. 3132-3142
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Tidskriftsartikel (refereegranskat)abstract
- Interactive effects between allelic variants of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) and stressors on depression symptoms have been documented, as well as questioned, by meta-analyses. Translational models of constitutive 5-htt reduction and experimentally controlled stressors often led to inconsistent behavioral and molecular findings and often did not include females. The present study sought to investigate the effect of 5-htt genotype, maternal separation, and sex on the expression of stress-related candidate genes in the rat hippocampus and frontal cortex. The mRNA expression levels of Avp, Pomc, Crh, Crhbp, Crhr1, Bdnf, Ntrk2, Maoa, Maob, and Comt were assessed in the hippocampus and frontal cortex of 5-htt± and 5-htt+/+ male and female adult rats exposed, or not, to daily maternal separation for 180 min during the first 2 postnatal weeks. Gene- and brain region-dependent, but sex-independent, interactions between 5-htt genotype and maternal separation were found. Gene expression levels were higher in 5-htt+/+ rats not exposed to maternal separation compared with the other experimental groups. Maternal separation and 5-htt+/− genotype did not yield additive effects on gene expression. Correlative relationships, mainly positive, were observed within, but not across, brain regions in all groups except in non-maternally separated 5-htt+/+ rats. Gene expression patterns in the hippocampus and frontal cortex of rats exposed to maternal separation resembled the ones observed in rats with reduced 5-htt expression regardless of sex. These results suggest that floor effects of 5-htt reduction and maternal separation might explain inconsistent findings in humans and rodents.
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| 4. |
- Granholm, Linnea, et al.
(författare)
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The expression of opioid genes in non-classical reward areas depends on early life conditions and ethanol intake
- 2017
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1668, s. 36-45
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Tidskriftsartikel (refereegranskat)abstract
- The young brain is highly sensitive to environmental influences that can cause long-term changes in neuronal function, possibly through altered gene expression. The endogenous opioid system continues to mature after birth and because of its involvement in reward, an inadequate maturation of this system could lead to enhanced susceptibility for alcohol use disorder. Recent studies show that the classical reward areas nucleus accumbens and ventral tegmental area are less affected by early life stress whereas endogenous opioids in non-classical areas, e.g. dorsal striatum and amygdala, are highly responsive. The aim was to investigate the interaction between early life conditions and adult voluntary ethanol intake on opioid gene expression. Male Wistar rats were exposed to conventional rearing, 15, or 360min of daily maternal separation (MS) postnatal day 1-21, and randomly assigned to ethanol or water drinking postnatal week 10-16. Rats exposed to early life stress (MS360) had increased opioid receptor gene (Oprm1, Oprd1 and Oprk1) expression in the dorsal striatum. Ethanol drinking was associated with lower striatal Oprd1 and Oprk1 expression solely in rats exposed to early life stress. Furthermore, rats exposed to early life stress had high inherent Pomc expression in the amygdala but low expression after ethanol intake. Thus, adverse events early in life induced changes in opioid gene expression and also influenced the central molecular response to ethanol intake. These long-term consequences of early life stress can contribute to the enhanced risk for excessive ethanol intake and alcohol use disorder seen after exposure to childhood adversity.
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| 5. |
- Nylander, Ingrid, 1957-, et al.
(författare)
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Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans
- 2017
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Ingår i: Molecular Neurobiology. - : Humana Press. - 0893-7648 .- 1559-1182. ; 54:8, s. 6225-6234
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.
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| 6. |
- Vrettou, Maria, et al.
(författare)
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DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early-life stress and adult ethanol exposure : an explorative study
- 2021
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Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
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| 8. |
- Vrettou, Maria, 1988-
(författare)
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Early life experiences and alcohol use in youth : An emerging role of the Vesicular Glutamate Transporters
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Initiation of alcohol consumption usually takes place during adolescence, a period characterized by a plethora of physical and emotional changes. Towards early adulthood, hazardous drinking patterns can emerge and potentially lead to the development of Alcohol Use Disorder (AUD). Both positive and negative experiences during early life can shape brain development and, through interactions with the genetic make-up, can contribute to the vulnerability of an individual to develop AUD. Epigenetic mechanisms, such as DNA methylation, potentially mediate the effect of environmental influences on gene expression, thus serving as the missing link between gene, environment and phenotype. Among various neuroadaptive changes seen in AUD, those within the glutamatergic system appear particularly prominent, mainly in withdrawal and relapse states, but also in stress-related outcomes. The glutamatergic phenotype can be determined by the expression of the Vesicular Glutamate Transporters 1-3 (VGLUT1-3). To date, the relationship between early life experiences, alcohol consumption, and Vgluts/VGLUTs genes (rodents/humans) in the initial stage of alcohol consumption and during the sensitive period of late adolescence/young adulthood has not been investigated.The present thesis, based on three studies on rodents and one on humans, aimed to examine Vglut/VGLUT1-3 correlates of early life experiences and alcohol drinking during youth. The effect of co-exposure to nicotine, because of its high comorbidity with alcohol use, as well as the role of key DNA methylation-regulating genes was also investigated. The main finding showed that individuals exposed to early life stress were more sensitive to the effect of alcohol on Vglut1-3 mRNA expression and DNA methylation, as well as expression of the DNA methylation-regulating genes, in limbic and striatal brain regions, as compared with controls. In an independent sample, prolonged nicotine co-exposure with alcohol during adolescence was associated with higher Vglut2 expression in the ventral tegmental area of young adult rats. Lastly, the single nucleotide polymorphism rs2290045 in VGLUT2 was found to moderate the environmental sensitivity to alcohol-related problems in humans. Carriers of the minor allele (T) displayed differential susceptibility to the environment; increasing quality of parenting was associated with higher and lower alcohol-related problems in the absence and presence of previous maltreatment, respectively.In conclusion, the findings highlight for the first time the role of Vgluts/VGLUTs in early stress-mediated sensitivity towards alcohol consumption and alcohol-related problems during adolescence and young adulthood, and especially a potential Vglut2/VGLUT2-mediated molecular signature behind the interactive mechanisms of these two aversive environmental factors, as well as of nicotine co-exposure.
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| 9. |
- Vrettou, Maria, et al.
(författare)
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Vesicular glutamate transporter 2 expression in the ventral tegmental area of outbred male rats following exposure to nicotine and alcohol
- 2023
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Ingår i: DRUG AND ALCOHOL DEPENDENCE REPORTS. - : Elsevier. - 2772-7246. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Initiation of use/co-use of nicotine and alcohol, commonly occurring in an episodic manner during adolescence, can imprint vulnerability to the developing brain and lead to addiction. The ventral tegmental area (VTA) is a key heterogeneous region of the mesocorticolimbic circuit involved in the binge-drinking and intoxication step of the addiction circuit. Higher human post-mortem VTA expression of vesicular glutamate transporter 2 (VGLUT2), a marker of the glutamatergic phenotype also expressed in dopaminergic [Tyrosine Hydroxylase (Th)-positive] neurons, has been associated with chronic nicotine use and co-use with alcohol. Methods: The present study aimed to map and characterize the Vglut2- and Th-expressing neurons in the VTA of adolescent male rats exposed or not to prolonged (six-weeks) episodic (three consecutive days/week) nicotine and/or alcohol administration. Nicotine (0.35 mg/kg free base) was injected subcutaneously, whereas alcohol (2 g/kg 20%) was administrated via gavage. Vglut2 and Th mRNA was assessed in the anterior and posterior VTA by use of in situ hybridization. Results: The profile of neurons varied with substance-exposure among VTA subregions. Th-only expressing neurons were more abundant in the posterior VTA of the group exposed to nicotine-only, compared to controls. The same neurons were, on the contrary, less present in the anterior VTA of animals exposed to alcohol-only, who also displayed a higher number of Vglut2-expressing neurons in the lateral anterior VTA. Conclusions: VTA Vglut2- and Th-only neurons seem differentially involved in the effects of adolescent episodic nicotine and alcohol exposure in the anterior and posterior VTA.
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