| 1. |
- Bendre, Megha
(author)
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Predictors of Alcohol Misuse : Role of MAOA Genotype, Methylation, Transcription, and Negative and Positive Environmental factors
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Alcohol misuse is a risk factor for alcohol use disorder (AUD). Gene-environment interactions contribute to the risk or resilience for AUD. A functional polymorphism in the promoter of the monoamine oxidase A gene (MAOA-uVNTR), in interaction with negative environment (Eneg), is associated with alcohol misuse and AUD. Men carrying short (MAOA-S), and women carrying long (MAOA-L), MAOA-uVNTR alleles who experienced maltreatment or poor parent-child relationships are at increased susceptibility to alcohol misuse and AUD. This thesis assessed whether the association of MAOAxEneg with the risk of AUD is moderated by MAOA methylation or positive environment and whether MAOA methylation-associated changes in MAOA expression in the stress- and reward-related brain regions is an underlying mechanism.The thesis reveals that the association of MAOAxEneg with alcohol misuse is moderated by MAOA methylation in men, but not in women. In the clinical sample, men carrying MAOA-S allele who experienced maltreatment and had low MAOA methylation displayed higher alcohol-related problems than those without maltreatment or MAOA-L carriers with and without maltreatment. Furthermore, the quality of the parent–child relationship moderated the association of MAOAxEneg with alcohol misuse in a sex- and AUD stage-dependent manner. In the non-clinical sample of adolescents, girls carrying MAOA-L allele who experienced maltreatment and poor parent–child relationship displayed higher alcohol consumption, whereas those with average or good parent–child relationship had lower alcohol consumption. In the clinical sample of adolescents, however, no such association was observed. These results suggest that a good parent–child relationship protects MAOA susceptibility genotype carriers exposed to maltreatment during the early stages of alcohol use. The preclinical studies revealed that the male rats exposed to Eneg and alcohol had higher CpG-specific Maoa promoter methylation, which was associated with lower Maoa expression in the nucleus accumbens than the control rats. Thus, MAOA methylation-associated changes in MAOA expression in the nucleus accumbens might mediate the effect of environment on alcohol use.The thesis contributes to the understanding of biological mechanisms underlying MAOAxEnvironment effect and the critical role of MAOA methylation and positive environment in moderating risk and resilience for AUD. Also, the identification of subgroups may benefit from personalised interventions for AUD.
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| 2. |
- Vadlin, Sofia, 1973-
(author)
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Problematic Gaming and Gambling among Adolescents
- 2016
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Doctoral thesis (other academic/artistic)abstract
- The overall aims of this thesis were to develop and evaluate a screening instrument designed to detect gaming addiction symptoms in adolescents, to study associations between problematic gaming and psychiatric symptoms, to investigate the stability of problematic gaming, and to examine possible associations between gaming at baseline (W1) with problem gambling three years later (W2).The study population consisted of adolescents from the Survey of Adolescent Life in Västmanland SALVe Cohort (adolescents in Västmanland born in 1997 and 1999, and their parents), in two waves (2012, n = 1887; 2015, n = 1576), and adolescents from child and adolescent psychiatric clinics in Västmanland (2014, n = 242).The development of the Gaming Addiction Identification Test (GAIT) was based upon the research literature on gaming, gambling, and addiction. An expert panel estimated the content validity of the GAIT and found it to be excellent. Additional psychometric evaluations of the GAIT and the parent version, GAIT-P, were conducted and it was found that both versions showed promising psychometric results, with high internal consistency, high concurrent validity, high concordance, unidimensionality, and high factor loadings, although poor model fit in exploratory factor analysis. Self- and parent-rated prevalence of gaming addiction symptoms were estimated at 1.3% with the GAIT and 2.4% with the GAIT-P in 13- and 15-year-olds.Self-rated problematic gaming above the cutoff had a boy to girl ratio of approximately 5:1 in both the SALVe Cohort and the clinical sample, whereas more girls than boys reported symptoms above the cutoff for ADHD, depression, anxiety, and psychotic-like-experiences. ADHD, depression, and anxiety symptoms were associated with odds ratios of 2.43, 2.47, and 2.06, respectively, in relation to coexisting problematic gaming. Furthermore, problematic gaming was stable over time, and problematic gaming at the first wave was associated with problem gambling three years later.It is important to screen for possible co-occurring symptoms among those who seek treatment and among those who appear to have symptoms of gaming, gambling, or psychiatric symptoms. Ongoing evaluation of adequate screening and diagnostic measurements, and the development and evaluation of treatments for problematic gaming, gaming addiction, and comorbid conditions are needed.
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| 3. |
- Immenschuh, Jana, 1994-
(author)
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Aromatase, sex hormones and the young adult brain
- 2024
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Doctoral thesis (other academic/artistic)abstract
- The enzyme aromatase coded by the gene CYP19A1/Cyp19a1 (humans/animals) catalyses the conversion of androgens into oestrogens, which play an important role in brain function from development through adulthood. Together with the sex hormones, aromatase seems to influence behaviour and cognition by affecting neurogenesis, differentiation, neuroplasticity, and neuroprotection. It is highly expressed in the limbic brain, suggesting a link to sex differences in mental health, including nicotine addiction, gambling disorder and resilience to early life stress (ELS) as well as structural properties of the brain. However, the underlying molecular mechanisms remain unclear. The studies of the present dissertation explored the distribution and influence of aromatase and sex hormones in rat and human brains, using different molecular biological methods, cognitive testing, as well as multimodal neuroimaging. Using fluorescence in-situ hybridization in the rat brain, Cyp19a1 expression was observed in the limbic regions and found to be higher in males compared to females, with the highest expression in the medial amygdala and the bed nucleus of the stria terminalis. Most Cyp19a1-expressing cells were GABAergic, some glutamatergic, and a small population of astrocytes expressing the gene was found. Furthermore, the expression of Cyp19a1 was observed to be lower in the medial prefrontal cortex (mPFC) of male rats exposed to ELS compared to controls, and a relationship between ELS and DNA methylation in the Cyp19a1 gene was detected. Using magnetic resonance imaging combined with [11C]cetrozole positron emission tomography in young adult women, aromatase availability (AA) was observed in the thalamus, the amygdala and the hypothalamus. A positive correlation with grey matter volume in those regions was found, together with a relationship between AA and the volume and cortical thickness of the mPFC and the volume and microstructure of the fornix. Additionally, an acute dose of nicotine was able to reduce AA in the thalamus. Experimental testing in young women showed an effect of menstrual cycle phase on reward-based decision-making and suggested a possible interaction between oestradiol and nicotine. In conclusion, these findings show for the first time in rats that aromatase is sex-, region- and cell type-specifically expressed and is affected by ELS. Moreover, in women aromatase is shown to be related to brain morphology and can be inhibited by nicotine, while fluctuating oestradiol influences cognition both alone and possibly in an interplay with nicotine. These findings advance our knowledge on the role of aromatase in the brain and the theoretical framework of psychoneuroendocrinology.
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