There is extensive research focused on identifying predictors of autism, including biomarkers such as genes and neurophysiology. Because of inconsistent data, I explored these biomarkers as predictors of variability in behavioral outcomes (i.e., internalizing and externalizing symptoms), rather than indicators of the disorder per se. In a sample of children (ages 8-16) diagnosed with High Functioning Autism (HFA) and an age- and IQ- matched typically developing comparison group, individual differences in behavioral outcomes were assessed in relation to common genetic polymorphisms, 5-HTTLPR and DRD4, and neurophysiological (ERN) and behavioral (rate of self-correction) measures of response monitoring. Although the diagnostic groups did not differ on allele frequency for 5-HTTLPR, carriers of the L variant displayed attenuated ERN amplitudes at frontal-central sites, lower rates of self-correction following errors, and higher levels of parent-reported Somatization and Hyperactivity. With respect to DRD4, an overrepresentation of the 7-repeat allele was found in the HFA sample. Regardless of diagnostic group, 7-repeat allele carriers were rated as having more attention problems. These results suggest that genetics and neural correlates of response monitoring may explain interindividual variations in social emotional functioning of both HFA and typically developing children alike. However, contrary to hypothesis, response monitoring did not mediate the association between 5-HTTLPR or DRD4 and outcome measures. Future directions of this research may look at how genes and measures of response monitoring affect etiology, course, and treatment of autism and other related disorders.

The diathesis-stress model focuses on the interaction between gene polymorphisms and negative environmental conditions (i.e., stressors); however, Belsky and Pluess (2009) recently proposed an alternative to diathesis-stress: the differential susceptibility hypothesis, which states that some individuals may be predisposed to be more adversely affected by negative environments but, also, to benefit more from positive environments. Nevertheless, the differential susceptibly hypothesis has not been rigorous tested. Thus, the purpose of this study was to test the differential susceptibility hypothesis by examining individual differences in men’s testosterone, behavioral, and psychological responses to social status as a function of the serotonin transporter promoter region polymorphism (5-HTTLPR), which was cited by Belsky and Pluess as a potential “plasticity gene” because one variant – the long (l) allele – appears to be associated with lower susceptibility/plasticity and another – the short allele (s) – appears to be associated with higher susceptibility/plasticity. In this study, groups of 3-4 male participants were allowed to socialize before being told that they were part of a larger initiative to create a student-run Honor Committee. They were asked to nominate one person to be the leader and one person to not be on the committee. Then, participants were told privately that everyone voted them to either (1) be the leader or (2) not be on the committee. Salivary hormone samples were collected at baseline and 20 minutes after vote feedback. In addition, after receiving the vote feedback, participants completed a series of dating anxiety and mate preference tasks and were given the option to examine an “actual honor violation” case either alone or as part of the committee. The results support the differential susceptibility hypothesis. In terms of testosterone response, ss individuals showed both greater reactivity and differential responses to vote feedback. Furthermore, the testosterone responses of ss individuals were moderated by basal cortisol, which is associated with approach/avoidance behavior (Kagan et al., 2003; Shoal, Giancola, & Kirillova, 2003). In addition, ss individuals’ decisions to work on the committee or work alone and responses to the mating tasks were dependent upon the vote feedback, whereas l-carriers’ decisions and responses were not. / text

Depression is a serious condition that affects a significant proportion of the population and causes substantial life impairment (Kessler et al., 2003). Cognitive models of depression vulnerability (e.g., Teasdale, 1988) posit that information processing biases for negative and positive stimuli play a critical role in the disorder. Change in negative thinking in response to dysphoric moods is referred to as cognitive reactivity and has been shown to be a risk factor for future increases in depression (e.g., Beevers & Carver, 2003; Segal et al., 2006). Interestingly, recent behavioral genetics research indicates that certain genes may influence cognitive factors associated with depression. The short allele of a polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with increased risk for depression in the context of life stress (Caspi et al., 2003); however, the psychological mechanisms that increase depression risk for short 5-HTTLPR allele-carriers have not been definitively identified. Recent work has begun to reveal an association between the 5-HTTLPR and cognitive factors associated with depression such as attention bias for emotional information (Beevers et al., 2007) and negative thinking style (Hayden et al., 2007). A pilot study (n = 156) revealed an association between 5-HTTLPR and cognitive reactivity for attention bias for happy faces. The current study (n = 180) extended and improved upon the pilot study’s methodology and examined the relationship between the 5-HTTLPR and cognitive reactivity for attention to sad and happy faces as well as cognitive reactivity for dysfunctional attitudes. Cognitive variables were assessed after a neutral mood induction and after a sad mood induction at two laboratory sessions separated by at least 24 hours. There was a significant association between the 5-HTTLPR and cognitive reactivity for attention bias for emotional faces among Caucasian participants. Specifically, the short allele was associated with increased bias for emotional faces after the sad mood induction compared to the neutral mood induction. There was a linear relationship between number of short alleles possessed by participants and increase in bias for emotional information. The 5-HTTLPR was not significantly associated with cognitive reactivity for dysfunctional attitudes, but the effect was in the expected direction. Results are discussed in the context of recent neuroimaging research and plasticity models of behavior genetics. Implications for a model of depression vulnerability integrating genetic, neural, and cognitive factors and future directions for similar behavioral genetics studies are discussed. / text

Made available in DSpace on 2014-06-12T22:58:47Z (GMT). No. of bitstreams: 2 arquivo4172_1.pdf: 2067262 bytes, checksum: 8951d5209bffa8c57c9f141b4137515a (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2008 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Estudos preliminares sugerem que há uma base biológica distinta para as nuances psicopatológicas dos transtornos do humor, tais como os sintomas somáticos, a lentificação psicomotora e as distorções cognitivas, inferidas através do Inventário Beck de Depressão (BDI). Nesse sentido, este estudo investigou a relação entre distorções cognitivas e a presença do polimorfismo genético 5-HTTLPR em pacientes com transtorno do humor (Depressão Maior, Distimia e Transtorno Bipolar). Este polimorfismo se caracteriza por uma variação de 44 pares de base de DNA na região reguladora do gene da proteína carreadora de serotonina e foi descrito há 15 anos atrás. Sua variante curta tem se mostrado como um importante fator de modulação de comportamentos patológicos em diversas síndromes neuropsiquiátricas e também em traços de personalidade, reação a fatores estressores e resposta a psicofármacos. A amostra estudada foi constituída por 20 pessoas, das quais 13 foram diagnosticadas com Distimia, dois com Depressão Maior e cinco com Transtorno Bipolar. Esses pacientes fazem parte de um grupo maior de indivíduos que foram genotipados para o 5-HTTLPR em um estudo precedente (OLIVEIRA et al., 2000) e que nesta análise atual foram convocados ao ambulatório de Saúde Mental do Hospital das Clínicas da UFPE, através de cartas e contatos realizados pela equipe dos PSFs (Programa de Saúde da Família) de cada Distrito Sanitário da região metropolitana do Recife. Os resultados da aplicação do BDI dos pacientes portadores da variante curta foram comparados com os dos pacientes que não apresentavam esta variante. Os resultados sugerem que os portadores da variante curta manifestam maior gravidade no quadro depressivo, bem como apresentaram maior propensão a demonstrar distorções cognitivas. Assim, o estudo aponta para uma correlação entre a variante curta do polimorfismo e a presença de distorções cognitivas

No description available.

The 5-HTT gene (SLC6A4) is regulated by a common polymorphism in the promoter region (5-HTTLPR), which has functional consequences. Two major alleles have been observed and shown to have differential transcriptional activity with the long (L) allele having greater gene expression than the short (S) allele. 5-HTTLPR appears to modulate depression, anxiety and personality traits such as neuroticism. Additionally, a significant influence of 5-HTTLPR genotype on amygdala reactivity in response to fearful stimuli has been reported. Moreover, 5-HTTLPR seems to impact on the role of stressful life events (SLEs) in the development of depression. An elevated risk of depression and suicidal behaviors has been found in carriers of at least one low expressing S allele who had experienced SLEs, suggesting a gene x environment interaction. However, a recent meta-analysis showed that several findings failed to replicate this finding. Since genetic polymorphisms of the dopaminergic and serotonergic neurotransmission interact at the molecular, analyses with another polymorphism of the dopaminergic system, the dopamine D4 receptor (DRD4) was included to consider these likely gene-gene interactions (epistasis). The aim of this series of studies was to investigate the role 5-HTTLPR and SLEs on the endocrine stress response in different age samples. While newborns have been examined by a heel prick, stress responses were provoked in children (8-12 yrs) and younger adults (19-31 yrs) and older adults (54-68 yrs.) with the Trier Social Stress Test (TSST). The Life History Calendar (LHC) and Life Events Questionnaire (LEQ) were used to acquire data on SLEs. While in newborns the S/S genotype showed a significantly higher acute endocrine stress response than L/L or S/L genotypes, no significant difference between genotype groups was found in children. In the younger adult sample, the genotype impacted on cortisol stress responsiveness was reversed. Adults carrying the more active L allele of the 5-HTTLPR polymorphism showed a significantly larger cortisol response to the TSST than individuals carrying at least one of the lower expressing S allele. In older adults, no significant difference between genotype groups was found. However, results point in the same direction with showing highest cortisol response in individuals with L/L genotype. These data suggest that the association between 5-HTTLPR and endocrine stress reactivity seems to alter across lifespan, more specific the effects of genotype turns around. In addition, a significant interaction effect of 5-HTTLPR and SLEs has been found in the sample of younger adults, i.e. that early SLE as well as a severe number SLEs across the entire lifespan seem to modulate the interaction between HPA axis activity and 5-HTTLPR genotype. Additionally, a DRD4 by 5-HTTLPR interaction emerged which point to independent and joint effects of these polymorphisms on stress responsivity with regard to the concept of genegene interaction.

This doctoral thesis investigated the role of the neuromodulator serotonin on four different value-based decision making tasks, using an acute tryptopahin intervention and an associative genetic approach - a naturally occuring variation in the promoter region of the serotonin transporter gene (5-HTTLPR). Additionally, structural (DTI) and functional aspects (BOLD-fMRI) of the brain were assessed using magnetic resonance imaging in relation to decision-making. Overall, we only found limited evidence for a serotonergic effect on decision-making that was restricted to a genetic association with risk-seeking for losses behaviour that could no be corroborated by differences in tonic serotonin levels or white matter microstructure. / In der vorliegenden Doktorarbeit wurde die Rolle des Neuromodulators Serotonin hinsichtlich vier verschiedener wertbasierter Entscheidungsfindungsaufgaben untersucht, wobei eine akute Tryptophanintervention und ein assoziativer genetischer Ansatz, eine natürlich vorkommende Variation in der Promoterregion des Serotonintransportergens (5-HTTLPR), zur Anwendung gekommen sind. Zusätzlich wurden strukturelle (DTI) und funktionelle Aspekte (BOLD-fMRI) des Gehirns mittels Magnetresonanztomographie in Bezug auf die Entscheidungsfindung erhoben. Insgesamt fanden wir nur eine begrenzte Evidenz eines serotonergen Effekts auf Entscheidungsverhalten, die sich auf eine genetische Assoziation mit risikofreudigem Verhalten bei Verlusten beschränkte. Diese Assoziation ließ sich nicht durch Unterschiede im tonischen Serotoninspiegel oder der Mikrostruktur der weißen Substanz erhärten.

Background: Serotonin has been implicated in impulsive behaviours such as temporal discounting. While animal studies and theoretical approaches suggest that reduced tonic serotonin levels increase temporal discounting rates and vice versa, evidence from human studies is scarce and inconclusive. Furthermore, an important modulator of serotonin signalling, a genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR), has not been investigated for temporal discounting so far. Objective: First, the purpose of this study was to test for a significant association between 5-HTTLPR and temporal discounting. Second, we wished to investigate the effect of high/low tonic serotonin levels on intertemporal choice and blood oxygen-level-dependent response, controlling for 5-HTTLPR. Methods: We tested the association of 5-HTTLPR with temporal discounting rates using an intertemporal choice task in 611 individuals. We then manipulated tonic serotonin levels with acute tryptophan interventions (depletion, loading, balanced) in a subsample of 45 short (S)-allele and 45 long (L)/L-allele carriers in a randomised double-blind crossover design using functional magnetic resonance imaging and an intertemporal choice task. Results: Overall, we did not find any effect of serotonin and 5-HTTLPR on temporal discounting rates or the brain networks associated with valuation and cognitive control. Conclusion: Our findings indicate that serotonin may not be directly involved in choices including delays on longer timescales such as days, weeks or months. We speculate that serotonin plays a stronger role in dynamic intertemporal choice tasks where the delays are on a timescale of seconds and hence are therefore directly experienced during the experiment.

The study aims to replicate the previous found association of 5-HTTLPR and inertia of negative affect in daily life of adolescents and young adults. Data of 877 adolescents (aged 14–21 years) of the Behavior and Mind Health (BeMIND) study (epidemiological cohort study, Dresden, Germany) were genotyped for 5-HTTLPR/rs25531, grouped into SS/SLG/SLA/ LGLA/LGLG vs. LALA, and provided ratings on negative affect items, depression and anxiety (Patient-Reported Outcomes Measurement Information System) eight times a day over 4 days. Multilevel regression models did not reveal an association of 5-HTTLPR genotype and inertia of negative affect, nor associations with inertia of anxiety or depression. Inertia of negative affect seems not to be a psychological mechanism through which 5-HTTLPR acts on psychopathology.

Mental health has become a prominent issue in society. Yet, much remains unknown about the etiology of psychiatric disorders. The aim of the present thesis was to investigate the association between biological, psychological and social factors of risk and resilience and behavioral problems in a birth cohort of Swedish children. 1723 mothers and their children were followed from birth to the age of 12 as part of the South East Sweden Birth Cohort Study (the SESBiC study). Information was gathered through register data, standardized questionnaires and DNA samples. In study I, stability of maternal symptoms of depression and the impact on child behavior at age 12 were investigated. The prevalence of depressive symptoms was found to be 12.0 % postpartum. Symptoms of postpartum depression significantly increased the risk for subsequent depressive symptoms 12 years later in women. Children whose mothers reported concurrent symptoms of depression and anxiety had an increased risk for both internalizing and externalizing problems at age 12, but no long term effect on child behavior was seen for postpartum depressive symptoms. The greatest risk was seen for children whose mothers reported symptoms of depression on both occasions. In study II, the impact of gene-environment interaction of 5-HTTLPR and BDNF Val66Met and experience of life events together with symptoms of maternal depression and anxiety on child behavior at age 12 was studied. A main effect of 5-HTTLPR was noticed, but no geneenvironment effects were shown. Similarly to study I, concurrent symptoms of maternal depression and anxiety were an important predictor of child behavioral problems. A high degree of psychosocial stress around childbirth was found to have long lasting detrimental effects on child behavior, increasing the risk for internalizing problems at age 12. Study III investigated the impact of geneenvironment interactions of 5-HTTLPR and BDNF Val66Met and life events together with symptoms of maternal depression and birth characteristics on behavioral problems at age 3. Symptoms of postpartum depression were found to predict internalizing as well as externalizing problems in children three years later. Child experience of life events was a stable predictor of behavioral problems across the scales similar to sociodemographic factors such as parental immigration status and unemployment. No gene-environment interaction effects of 5-HTTLPR or BDNF Val66Met were shown. Study IV used the risk factors identified in studies I-III to investigate factors of resilience to behavioral problems at age 12. The l/l genotype of 5-HTTLPR was associated with a lower risk for behavioral problems at age 12, especially for children facing low adversity. Good social functioning was found to be a general resource factor, independent of the level of risk, while an easy temperament was associated with resilience for children with a high degree of adversity. However, effect sizes were small. In summary, the results from the present thesis emphasize the importance of maternal mental health and sociodemographic factors for child mental health at ages 3 and 12, which must be taken into account in clinical settings. Moreover, it adds to the null-findings of the gene-environment effect of 5-HTTLPR and BDNF Val66Met on behavioral problems in children, but indicates a main effect of 5-HTTLPR on internalizing symptoms at age 12.