Certains gènes, modulant la sérotonine (5-hydroxytryptamine, 5-HT), ont été associés aux tempéraments liés à l'anxiété. Une limitation dans la plupart de ces études est que les études sont de nature transversale et l'anxiété a été évaluée à un seul point dans le temps. De plus, seules quelques études ont été réalisées chez les enfants. Le but de la présente étude était d'étudier le rôle des gènes HTR2A et TPH2 dans le développement des trajectoires d’anxiété durant l’enfance. Les associations entre ces gènes, ces trajectoires, le diagnostic d’anxiété à l'âge adulte et les différences entre les sexes ont été examinées dans l'Étude Longitudinale des Enfants de Maternelle au Québec, composée de 3185 enfants recrutés en 1986-1987. Leur anxiété a été cotée par leur professeur annuellement entre 6 et 12 ans. Ces cotes ont été modélisées en trajectoires comportementales. Les données genotypées de 5-HT, disponibles pour 1068 personnes, ont été analysées en utilisant les statistiques du Chi-carré, des régressions logistiques et des analyses de variance. Sur les 37 polymorphismes étudiés, plusieurs ont été associés à la trajectoire de forte anxiété, tels le 5-HTR2A (rs1328684, rs95534511, rs1745837, rs7984966, 7330636) et TPH2 (rs11179050, rs11179052, rs1386498). Bien que les trajectoires d’anxiété en enfance n’aient pas prédit le diagnostic d'anxiété à 21 ans, les relations ont été trouvées entre ce diagnostic, HTR2A et les polymorphismes du nucléotide simple (PNS) de TPH2. On remarque que les PNS associés à l’anxiété durant l’enfance et l’âge adulte ne sont pas les mêmes. La force d'association entre les gènes étudiés et l'anxiété diffère entre les garçons et les filles. Cette étude est la première à identifier une association entre les variantes TPH2, 5-HTR2A et les trajectoires d’anxiété en enfance. Les études futures devraient reproduire les résultats dans d'autres échantillons, enquêter sur l'interaction avec les facteurs de stress, et étudier la pertinence fonctionnelle de la PNS. / A number of genes known to modulate serotonin (5-hydroxytryptamine, 5-HT) have been associated with anxiety-related temperaments. A limitation in most of these studies is that the studies are cross-sectional and anxiety has been measured at a single point in time. Furthermore, only a few studies have been done in children. The aim of the present study was to investigate the role of the HTR2A and TPH2 gene in the development of trajectories of anxiety in childhood/ adolescence. Associations between these genes, anxiety trajectories in childhood and anxiety diagnoses in adulthood were also investigated. Finally, gender differences were explored. Research questions were investigated in the Quebec Longitudinal Study of Kindergarten Children, consisting of 3185 boys and girls, selected in 1986-1987. Children`s anxiety was rated by their teacher every year between the age of 6 and 12 years. The ratings were modeled into behavioral trajectories. 5-HT genotyping data were available for 1068 cohort members. Data were analyzed using Chi-square statistics, logistic regressions and ANOVAs. Out of 37 investigated polymorphisms, several polymorphisms, such as 5-HTR2A (rs1328684, rs95534511, rs1745837, rs7984966, 7330636) and TPH2 (rs11179050, rs11179052, rs1386498) were associated with a high anxiety trajectory. Though trajectories of high anxiety in childhood did not predict an anxiety diagnosis at age 21, relationships were found between HTR2A and TPH2 SNPs and anxiety diagnosis at age 21. We note that the SNPs associated with anxiety were different between adults and children. The strength of association between the investigated genes and anxiety differed between boys and girls. This is the first study reporting an association with some HTR2A and TPH2 variants and trajectories of anxiety in children. Future studies should replicate the findings in other samples, investigate the interaction with stressors, and study the functional relevance of the SNPs

Vitamin A and its derivatives, known as retinoids, are involved in a number of functions in the developing and adult brain (Lane et al., 2005). Roaccutane (13-cis-retinoic acid, 13-cis-RA) is a synthetic retinoid used for the treatment of severe cystic acne, although its use has been controversially associated with adverse psychiatric events including depression. In this thesis, the presence of retinoid receptors in the rat hippocampus was verified and a similar profile of expression was observed in the rat raphe nuclei for the first time. The expression of retinoid receptors in brain regions that are implicitly associated with depression pathology provides proof of concept for retinoids to influence depressive behaviour. The ability of 13-cis-RA treatment to induce a pro-depressive profile in animal models of depression-related behaviour was tested. In the resident-intruder paradigm, adult rats treated for 7 or 14 days with 13-cis-RA (1mg/kg, i.p.) showed reduced aggressive behaviour, with a concomitant increase in flight submit and flight escape behaviours, compared with vehicle-treated controls. These findings are indicative of increased depression-related behaviour. However, chronic treatment did not alter depression-related behaviour in the forced swim test and sucrose consumption anhedonia paradigms The molecular mechanisms mediating 13-cis-RA-induced depression were investigated by examining monoaminergic gene expression, protein levels and neurotransmitter levels in rat brain tissue and plasma and an in vitro model. The majority of serotonergic components (SERT, 5-HT1AR, 5-HT1BR and MAOA) were not altered by chronic 13-cis-RA treatment, with the possible exception of TPH2 gene/protein expression and increased 5-HT levels in platelets. In fact, the expression of D2 dopamine receptor was significantly elevated in the RN46A-B14 cell line (10μM 13-cis-RA, 48 h) and was similarly elevated at the protein level in the juvenile rat hippocampus (1mg/kg/day, i.p., 6 weeks), suggesting dopaminergic pathways may be of importance. There was also a trend in the data to suggest that 13-cis-RA-treated juvenile rats may be more susceptible the molecular alterations than corresponding adult rats. xii

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-04-04T15:05:19Z No. of bitstreams: 1 SAMARA MARQUES DOS REIS .pdf: 1152921 bytes, checksum: 30f5b5e9c3afbab29666da7f6e7c9033 (MD5) / Made available in DSpace on 2016-04-04T15:05:19Z (GMT). No. of bitstreams: 1 SAMARA MARQUES DOS REIS .pdf: 1152921 bytes, checksum: 30f5b5e9c3afbab29666da7f6e7c9033 (MD5) Previous issue date: 2015-03-04 / Estudos de associação gene-doença mostraram uma relação entre TPH2 e a depressão em diferentes populações, estudos, no entanto, têm sido produzidos resultados contraditórios, sendo a Triptofano hidroxilase-2 (TPH2) uma enzima limitante da taxa na via sintética para a serotonina do cérebro, vários estudos relatam os polimorfismos da enzima TPH2. Dois grandes projetos, o HapMap e o 1000 genomas, organizaram a maioria dos polimorfismos a partir do estudo de várias populações disponibilizando estes dados. Este trabalho tem como objetivo desenvolver um método de estudo para obtenção de possíveis marcadores de predisposição a doença a partir da correlação entre os dados epidemiológicos e frequências populacionais de polimorfismos, baseado na hipótese de que se numa população existe maior frequência de uma determinada patologia determinada geneticamente, então as variantes envolvidas deveriam estar em maior frequência e vice-versa. O modelo usado foi o envolvimento de variantes do gene TPH2 na predisposição à depressão. Os dados obtidos com correlação positiva em um dos genótipos homozigotos e também no alelo deste homozigoto sugeriram a presença de 10 polimorfismos (14,49% do total) possivelmente envolvidos no desenvolvimento do processo depressivo. Estes dados foram comparados com dados da literatura envolvendo estudos do tipo caso controle. Nestes trabalhos foram estudados 20 dos 69 polimorfismos descritos para o gene TPH2. Com exceção de um único polimorfismo, todos os dados obtidos com a nossa estratégia apresentaram-se iguais aos dados da literatura, inclusive quanto ao alelo que determinaria predisposição à depressão quando demonstrada associação. Portanto, propomos esta estratégia como uma forma alternativa de se realizar estudos do tipo Genome-Wide Association sem a necessidade de estudos caso-controle, apenas usando dados epidemiológicos da doença, diminuindo o tempo e custo destes estudos. / Disease-gene association studies reported a relation between the TPH2 and depression in different populations, however some studies have produced contradictory results, being the tryptophan hydroxylase-2 (TPH2) a limiting enzyme in the rate of synthetic route of serotonin in the brain, many studies reported the polymorphisms of the TPH2 enzyme. Two big projects, HapMap and 1000 genomes, organized the major part of these polymorphisms from the study of several populations becoming these data available. This work is aimed to develop a system to obtain possible predisposition markers of a disease from the correlation between epidemiological data and population frequencies of polymorphism, based in the hypothesis that if in a population there is more frequency of a certain kind of pathology genetically determined, the variables involved should be more frequent and vice-versa. The model used was the involvement of variables of the TPH2 gene in the predisposition of depression. The data obtained with positive correlation in one of homozygous genotypes and in the allele of this homozygous suggested the presence of 10 polymorphisms (total 14,49%) possibly related to the development of depression. These data were compared to literature data involving case control studies. In these work were studied 20 from 69 polymorphisms described to the TPH2 gene. With the exception of only one polymorphism, all the data obtained through the strategy proposed in this work have been equals to the literature data, including the allele that is determinant to the predisposition of depression when it is demonstrated the association. Therefore, it is proposed this strategy as an alternative to realize this kind of Genome-Wide Association studies without the necessity of a case control study, only using the epidemiological data from the disease, decreasing the time and the cost of this study.

Certains gènes, modulant la sérotonine (5-hydroxytryptamine, 5-HT), ont été associés aux tempéraments liés à l'anxiété. Une limitation dans la plupart de ces études est que les études sont de nature transversale et l'anxiété a été évaluée à un seul point dans le temps. De plus, seules quelques études ont été réalisées chez les enfants. Le but de la présente étude était d'étudier le rôle des gènes HTR2A et TPH2 dans le développement des trajectoires d’anxiété durant l’enfance. Les associations entre ces gènes, ces trajectoires, le diagnostic d’anxiété à l'âge adulte et les différences entre les sexes ont été examinées dans l'Étude Longitudinale des Enfants de Maternelle au Québec, composée de 3185 enfants recrutés en 1986-1987. Leur anxiété a été cotée par leur professeur annuellement entre 6 et 12 ans. Ces cotes ont été modélisées en trajectoires comportementales. Les données genotypées de 5-HT, disponibles pour 1068 personnes, ont été analysées en utilisant les statistiques du Chi-carré, des régressions logistiques et des analyses de variance. Sur les 37 polymorphismes étudiés, plusieurs ont été associés à la trajectoire de forte anxiété, tels le 5-HTR2A (rs1328684, rs95534511, rs1745837, rs7984966, 7330636) et TPH2 (rs11179050, rs11179052, rs1386498). Bien que les trajectoires d’anxiété en enfance n’aient pas prédit le diagnostic d'anxiété à 21 ans, les relations ont été trouvées entre ce diagnostic, HTR2A et les polymorphismes du nucléotide simple (PNS) de TPH2. On remarque que les PNS associés à l’anxiété durant l’enfance et l’âge adulte ne sont pas les mêmes. La force d'association entre les gènes étudiés et l'anxiété diffère entre les garçons et les filles. Cette étude est la première à identifier une association entre les variantes TPH2, 5-HTR2A et les trajectoires d’anxiété en enfance. Les études futures devraient reproduire les résultats dans d'autres échantillons, enquêter sur l'interaction avec les facteurs de stress, et étudier la pertinence fonctionnelle de la PNS. / A number of genes known to modulate serotonin (5-hydroxytryptamine, 5-HT) have been associated with anxiety-related temperaments. A limitation in most of these studies is that the studies are cross-sectional and anxiety has been measured at a single point in time. Furthermore, only a few studies have been done in children. The aim of the present study was to investigate the role of the HTR2A and TPH2 gene in the development of trajectories of anxiety in childhood/ adolescence. Associations between these genes, anxiety trajectories in childhood and anxiety diagnoses in adulthood were also investigated. Finally, gender differences were explored. Research questions were investigated in the Quebec Longitudinal Study of Kindergarten Children, consisting of 3185 boys and girls, selected in 1986-1987. Children`s anxiety was rated by their teacher every year between the age of 6 and 12 years. The ratings were modeled into behavioral trajectories. 5-HT genotyping data were available for 1068 cohort members. Data were analyzed using Chi-square statistics, logistic regressions and ANOVAs. Out of 37 investigated polymorphisms, several polymorphisms, such as 5-HTR2A (rs1328684, rs95534511, rs1745837, rs7984966, 7330636) and TPH2 (rs11179050, rs11179052, rs1386498) were associated with a high anxiety trajectory. Though trajectories of high anxiety in childhood did not predict an anxiety diagnosis at age 21, relationships were found between HTR2A and TPH2 SNPs and anxiety diagnosis at age 21. We note that the SNPs associated with anxiety were different between adults and children. The strength of association between the investigated genes and anxiety differed between boys and girls. This is the first study reporting an association with some HTR2A and TPH2 variants and trajectories of anxiety in children. Future studies should replicate the findings in other samples, investigate the interaction with stressors, and study the functional relevance of the SNPs

The placebo effect, a beneficial effect attributable to a treatment containing no specific properties for the condition being treated, has been demonstrated in a variety of medical conditions. This thesis includes four studies aimed at increasing our knowledge on the neurobiology of placebo. Study I, a review of the placebo neuroimaging literature, suggested that the anterior cingulate cortex (ACC) may be a common site of action for placebo responses. However, because placebo neuroimaging studies in clinical disorders are largely lacking, the clinical relevance of this needs further clarification. The subsequent three empirical studies were thus designed from a clinical perspective. Using positron emission tomography (PET) these studies investigated the underlying neurobiology of sustained placebo responses in patients with social anxiety disorder (SAD), a disabling psychiatric condition that nonetheless may be mitigated by placebo interventions. Study II demonstrated that serotonergic gene polymorphisms affect anxiety-induced neural activity and the resultant placebo phenotype. In particular, anxiety reduction resulting from placebo treatment was tied to the attenuating effects of the TPH2 G-703T polymorphism on amygdala activity. Study III further compared the neural response profile of placebo with selective serotonin reuptake inhibitors (SSRIs), i.e the first-line pharmacological treatment for SAD. A similar anxiety reduction was noted in responders of both treatments. PET-data further revealed that placebo and SSRI responders had similar decreases of the neural response in amygdala subregions including the left basomedial/basolateral (BM/BLA) and the right ventrolateral (VLA) sections. To clarify whether successful placebo and SSRI treatments operate via similar or distinct neuromodulatory pathways, study IV focused on the connectivity patterns between the amygdala and prefrontal cortex that may be crucial for normal emotion regulation. In responders of both treatment modalities, the left amygdala (BM/BLA) exhibited negative coupling with the dorsolateral prefrontal cortex and the rostral ACC as well as a shared positive coupling with the dorsal ACC. This may represent shared treatment mechanisms involving improved emotion regulation and decreased rumination. This thesis constitutes a first step towards better understanding of the neurobiology of placebo in the treatment of anxiety, including the neural mechanisms that unite and segregate placebo and SSRI treatment.

No description available.

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.

Serotonin gilt als Hauptangriffsstelle gängiger Antidepressiva bei schweren Depressionen, wie bspw. selektive Serotonin-Wiederaufnahmehemmer (SSRI), und -Enhancer (SSRE). Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (spez. Brain derived neurotophic factor, BDNF) oder die Hypothalamus-Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen Serotoninsystems bei schweren Depressionen, ein Rückgang der Neurogenese im Gyrus dentatus des Hippocampus einhergeht. Ziel dieser Arbeit war, das Zusammenspiel von Serotonin, BDNF, adulter Neurogenese und der Stressachse zu untersuchen. Zentrum der Studien ist ein Mausmodell, mit einer genetischen Depletion des zentralen Serotonin-synthetisierenden Enzyms Tryptophanhydroxylase 2 (sog. Tph2-/- Mäuse). Es wurden die physiologische Reaktionen auf die Behandlung mit gängigen Antidepressiva abhängig von der Abwesenheit von Serotonin untersucht, um mögliche alternative Signalwege aufzeigen zu können. Die bekannte Zunahme der Neurogenese nach SSRI/SSRE-Behandlung wurde in Wildtyptieren beobachtet, während die Therapie in Tph2-/- Mäusen keine direkte kausale Wirkung zeigte. Im Gegensatz dazu waren die BDNF-Spiegel in depressionsrelevanten Hirnregionen in Tph2-/- Mäusen nach SSRI, signifikant verringert. Auch zeigen die Studien eine neurobiologische Relevanz von Serotonin im ZNS, bei den antidepressiven Mechanismen einer Elektrokonvulsiven Krampftherapie. Ebenfalls deuten erhöhte Neurogeneseraten bei lebenslanger Abwesenheit von Serotonin im ZNS, Therapiemethoden-unabhängig, möglicherweise auf eine modulierte Stressreaktion hin. Untersuchungen der Parameter des HPA-Stressachsensystems, wiesen auf einen grundlegend veränderten Stresshormonspiegel in Tph2-/- Mäusen hin. / Serotonin, the "molecule of happiness" is an important target for antidepressants. The mainly prescribed drugs in major depression are selective serotonin re-uptake inhibitors (SSRI); but recently, SSR-enhancer (SSRE) have also attracted clinical attention. However, only a quarter of patients responds to treatment. It needs to be determined, whether SSRI/E act solely via manipulating serotonin levels or whether other pathways are involved, e.g. neurotrophic signaling (brain-derived neurotrophic factor, BDNF) or the hypothalamus-pituitary-adrenal (HPA)-axis. Furthermore, in major depression, dysregulation of central serotonin signaling is accompanied with a decline in hippocampal neurogenesis, as has been observed in rodent models. At the center of this thesis is a mouse model deficient in the central serotonin-synthesizing enzyme, tryptophan hydroxylase 2 (Tph2-/- mice). I have investigated physiological responses to antidepressant treatment in the absence of brain serotonin, and the possible role of alternative pathways. I observed the typical increase in neurogenesis upon SSRI treatment in WT mice, while it had no effect in Tph2-/- mice. In contrast, BDNF levels were significantly decreased in Tph2-/- mice after treatment with no effect in WT control mice. Furthermore, my results show a critical role of brain serotonin in the neurobiological effects of electroconvulsive seizure. Surprisingly, in animals lacking central serotonin, increased neurogenesis was observed independently of the treatment. The gathered data indicated an altered stress response; therefore, parameters of the HPA-axis have been studied, indicating a downregulated HPA system in Tph2-/-animals in baseline state, but showed no difference in treatment or feedback control. This thesis gives insight into the mechanisms of antidepressant action and reveals ideas for novel pathways involved in the process that could be used as targets in therapeutic approaches and further research in major depression.