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Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

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.

Major depressive disorder (MDD) will soon represent the most costly and debilitating disorder in the world. Yet, a clear model of the mechanisms underlying MDD remains elusive. This lack of clarity obscures efforts to prevent and treat MDD more effectively. This dissertation seeks to advance an integrated model of the mechanisms underlying MDD across cognitive, neural, and genetic levels of analysis. Building on the empirical foundation of cognitive theories of MDD, the dissertation includes three studies that help address questions about the cognitive mechanisms underlying depression vulnerability and maintenance. Specifically, the three studies focus on identifying 1) how elaborative processing biases, including attentional biases and rumination, give rise to specific symptoms of MDD and 2) elucidating biological mechanisms that may give rise to these biases. Together, these studies help advance an integrated model of MDD that, ultimately, may help facilitate the prevention and treatment of this costly and debilitating disorder. / text

Memory monitoring, or the ability to accurately assess one’s memory retrieval success, is known to be declined for older adults. The behavioral decline has been well explored, and is specific to tasks of source monitoring; tasks involving item memory monitoring do not show age-related deficits. This study attempts to further characterize the decline by exploring neuroanatomical contributions to the decline, and genetic influences that may explain performance variability in older adults. Older adults were genotyped for the serotonin transporter (5-HTTLPR) gene, and those that are carriers of the low-expressing allele demonstrate the expected age-related decline of source monitoring performance when compared to younger adults. Interestingly, older adults who lack this allele did not display any decline in performance when compared to younger adults. Neuroanatomical correlates of task performance indicate that prefrontal regions in the inferior and lateral cortices support accurate source memory monitoring, likely through their role in the proper selection of memory cues and inhibition of irrelevant information. This relationship suggests that age-related atrophy occurring in these structures could be responsible for the performance deficits on source memory monitoring tasks. There was no direct relationship seen between genotype for the 5-HTTLPR gene and cortical volumes, however diffusion tensor imaging shows that older adults who carry this allele have altered connections between the medial temporal lobe, responsible for memory retrieval, and prefrontal cortex, which monitors the retrieval process. Through stronger connections of critical networks, older adults who lack the 5-HTTLPR short allele may be able to compensate for the age-related atrophy seen in the prefrontal cortex. Functional results further indicate that the older adult non-carriers recruit inferior and lateral frontal regions to a greater extent than the older adult carriers during accurate memory monitoring. These results begin to suggest a neuroprotective mechanism for the 5-HTTLPR genotype, wherein some older adults may be able to postpone the expected decline of memory monitoring by retaining the ability to recruit essential inferior frontal structures through more organized white matter pathways. / text

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Introdução: A religiosidade e espiritualidade (R/E) são aspectos importantes na vida e cultura de grande parte da população. Embora as práticas religiosas sejam universais e evidências demostrem sua importância clínica, as bases biológicas desse comportamento são pouco investigadas, particularmente a níveis genéticos. Objetivos: Verificar a associação dos polimorfismos 5-HTTLPR, SNP na região UTR 3’ (rs3813034) do gene 5-HTT, Val66Met do gene BDNF e repetições do éxon III do gene DRD4 com mediunidade e religiosidade/espiritualidade; além disso verificar a relação entre os polimorfismos gênicos de médiuns espíritas e grupo controle e traços de personalidade. Métodos: O estudo incluiu 130 voluntários, sendo 75 médiuns espíritas e 55 voluntários não médiuns do grupo controle. Foi distinguido os genótipos dos polimorfismos 5-HTTLPR, SNP rs3813034 do gene 5-HTT, Val66Met do gene BDNF e repetições do éxon III do gene DRD4. Os voluntários responderam questionários de Religiosidade P-DUREL, Inventário de Temperamento e Caráter de Cloninger (ITC) e Self-Report screening questionnaire (SRQ). Resultados: Amostras de médiuns espíritas tem alta religiosidade pela P-DUREL e altas pontuações nas dimensões de caráter do ITC comparadas ao grupo controle. Não houve diferença significativa entre SRQ+ de médiuns (20%) e grupo controle (26,8%). Não foi encontrado associação entre genótipos e mediunidade ou religiosidade pela P-DUREL. Houve associação entre os genótipos 5-HTTLPR, o SNP rs3813034 e repetições do gene DRD4 e subescalas da dimensão Autotranscendência (AT) de Cloninger. A subescala Identificação transpessoal se associou exclusivamente a genótipos de médiuns espíritas. Conclusão: Médiuns espíritas possuem personalidade associada a boa saúde mental e baixa prevalência de transtornos mentais. De acordo com os resultados obtidos há indicativo de que polimorfismos 5- HTTLPR, rs3813034 do gene 5-HTT e do DRD4 de médiuns afeta a dimensão de caráter autotranscendência da TCI. / Introduction: Religion and spirituality (R / E) are important aspects in the life and culture of a large part of the population. Although religious practices are universal and evidence demonstrates their clinical importance, the biological basis of such behavior is poorly investigated, particularly at genetic levels. Objectives: To verify the association of 5- HTTLPR, SNP polymorphisms in the 3 'UTR region (rs3813034) of the 5-HTT gene, Val66Met of the BDNF gene, and 48 bp repeats on exon III of the DRD4 gene with mediumship and religiosity / spirituality; In addition to verify the relationship between the gene polymorphisms of spiritist mediums and control group and personality traits. Methods: The study included 130 volunteers, 75 Spiritist mediums and 55 non-medium volunteers from the control group. Genotypes of the 5-HTTLPR polymorphisms, rs3813034 SNPs of the 5- HTT gene, Val66Met of the BDNF gene and exons of the exon III of the DRD4 gene were distinguished. The volunteers answered the following questionnaires: P-DUREL, Cloninger’s Temperament and Character Inventory (ITC) and Self-Report screening questionnaire (SRQ). Results: Spiritist mediums scored high religiosity in P-DUREL and high scores on the ITC’s character dimensions compared to the control group. There was no significant difference between SRQ + of mediums (20%) and control group (26.8%). There was no association between genotypes and mediumship or religiosity by P-DUREL. There was an association between the 5-HTTLPR genotypes, the rs3813034 SNP and DRD4 gene repetition and Cloninger's Autotranscendence (AT) subscales. The subscale Transpersonal Identification was exclusively associated with genotypes of spiritist mediums. Conclusion: Spiritist mediums have personality traits associated with good mental health and low prevalence of mental disorders. According to the results, there are indications that 5-HTTLPR and rs3813034 polymorphisms of the 5-HTT gene and the DRD4 can affect the character dimension of self-transcendence of the TCI when mediumship is present. / Tese (Doutorado)

L’objectif de cette thèse était de contribuer à l’avancement des connaissances quant aux circonstances permettant une transmission intergénérationnelle du risque émanant de l’adversité maternelle et aux mécanismes sous-tendant cette transmission, dans quatre articles empiriques. Le premier visait à explorer la relation entre un historique d’adversité maternelle, la sécurité d’attachement mère-enfant et le tempérament de l’enfant. Les mères ont complété une entrevue semi-structurée portant sur leurs représentations d’attachement avec leurs parents, à 6 mois, et ont évalué le tempérament de leur enfant à 2 ans. La sécurité d’attachement fut également évaluée à 2 ans. Les résultats ont démontré que les enfants dont les mères rapportaient des niveaux supérieurs d’adversité présentaient de moins bons niveaux d’activité comportementale, uniquement lorsqu’ils avaient un attachement sécurisant avec leur mère. Ces résultats suggèrent une transmission intergénérationnelle des effets d’un historique d’adversité maternelle sur le tempérament des enfants. Le deuxième article visait à investiguer si le transporteur de sérotonine (5-HTTLPR) module la transmission de risque intergénérationnelle de l’adversité maternelle sur le tempérament des enfants. L’historique d’adversité maternelle fut évalué en combinant deux mesures auto-rapportées. Les mères ont également évalué le tempérament de leur enfant à 18 et à 36 mois. Le génotype des enfants fut extrait à 36 mois. Les résultats ont révélé un effet d’interaction entre l’adversité maternelle et le génotype de l’enfant sur le tempérament, suggérant une transmission intergénérationnelle des effets de l’adversité maternelle sur le fonctionnement émotionnel des enfants. Le troisième article visait à explorer la relation entre les difficultés d’adaptation psychosociale des mères, la sensibilité maternelle et les symptômes intériorisés de leurs enfants. Les mères ont complété plusieurs questionnaires desquels un score composite de difficultés d’adaptation psychosociale fut extrait. La sensibilité maternelle fut observée à 12 mois. Les symptômes intériorisés des enfants furent évalués par les deux parents à 2 et à 3 ans. Les résultats ont démontré qu’une augmentation des difficultés maternelles d’adaptation psychosociale étaient associée à davantage de symptômes intériorisés chez les enfants, mais seulement chez ceux dont les mères étaient moins sensibles. Ces résultats ont été observés par les mères à 2 ans et par les deux parents à 3 ans. Ces résultats suggèrent que les enfants peuvent être différemment affectés par l’adaptation émotionnelle de leur mère tout en mettant l’emphase sur le rôle protecteur de la sensibilité maternelle. Le quatrième article visait à investiguer les rôles médiateurs de la dépression et de la sensibilité maternelle dans la relation entre un historique d’adversité maternelle et le tempérament de l’enfant. L’historique d’adversité maternelle fut évalué en combinant deux mesures auto-rapportées. Les mères ont également rapporté leurs symptômes dépressifs à 6 mois. La sensibilité maternelle fut évaluée de façon concomitante. Les mères ont évalué le tempérament de leur enfant à 36 mois. Les résultats ont révélé une transmission intergénérationnelle des effets d’un historique d’adversité maternelle à la génération suivante suivant une médiation séquentielle passant d’abord par la dépression maternelle et ensuite par la sensibilité maternelle. Finalement, les résultats des quatre articles ont été intégrés dans la conclusion générale. / The main goal of this dissertation was to document more extensively the circumstances under which intergenerational risk transmission of maternal adversity occurs and to identify underlying processes. The dissertation is comprised of four empirical articles. The first article examined the relation between maternal history of early adversity, mother-child attachment security, and child temperament. Mothers completed a semi-structured interview pertaining to their childhood attachment experiences with their parents at 6 months and rated their children’s temperament at 2 years. Mother-child attachment was also assessed at 2 years. Results showed that children whose mothers received higher scores of early life adversity displayed poorer temperamental activity level outcomes but only when they also showed high concomitant levels of attachment security, suggesting intergenerational effects of maternal early life experiences on child temperament. The second article examined the intergenerational effects of maternal childhood adversity on child temperament targeting the serotonin transporter polymorphism, 5-HTTLPR, as a potential moderator of those maternal influences. Maternal history of early adversity was assessed with an integrated measure derived from two self-report questionnaires. Mothers also rated their children’s temperament at 18 and 36 months. Child genotyping was performed at 36 months. Results yielded a significant interaction effect of maternal childhood adversity and child 5-HTTLPR genotype on child temperament, suggesting intergenerational effects of maternal history of adversity on child emotional function. The third article investigated the interactive effects of maternal psychosocial maladjustment and maternal sensitivity on child internalizing symptoms. Families took part in four assessments between ages 1 and 3 years. Mothers completed several questionnaires from which a composite score of maternal psychosocial maladjustment was derived. Maternal sensitivity was rated by an observer at 12 months. Child internalizing symptoms were assessed by both parents at 2 and 3 years. Results revealed that increased maternal psychosocial maladjustment was related to more internalizing symptoms in children, however only among children of less sensitive mothers whereas children of more sensitive mothers appeared to be protected. This was observed with maternal reports at 2 years, and both maternal and paternal reports at 3 years. These results suggest that young children may be differentially affected by their parents’ emotional adjustment, while highlighting the pivotal protective role of maternal sensitivity in this process. Finally, the fourth article examined the mediating roles of maternal depression and maternal sensitivity in the relation between maternal history of early adversity and child temperament. Maternal history of early adversity was assessed with an integrated measure derived from two self-report questionnaires. Mothers also reported on their depression symptoms at 6 months. Maternal sensitivity was rated concurrently. Mothers also completed a questionnaire on their children’s temperament at 36 months. Results suggested the intergenerational transmission of the effects of maternal childhood adversity to offspring occurs through a two-step, serial pathway, specifically through maternal depression, first, and, then, to maternal sensitivity. Finally, the results of the four articles were integrated into a general conclusion.