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Accumulating data indicate a common occurrence of tic exacerbations and periods of psychosocial stress. Patients with Tourette’s syndrome (TS) also exhibit aberrant markers of hypothalamic-pituitary-adrenal (HPA) axis activation. Based on these findings, a functional relationship between stress and tic disorders has been suggested, but the underlying mechanism of how stress may affect tic pathology remains to be elucidated. We suggest that dopaminergic and noradrenergic neurotransmission as well as immunology play a crucial role in mediating this relationship. Two possibilities of causal direction might be assumed: (a) psychosocial stress might lead to an exacerbation of tics via activation of HPA axis and subsequent changes in neurotransmission or immunology and (b) TS-related abnormalities in neurotransmission or immunology result in a higher vulnerability of affected

Background: Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders.

Allergic manifestations are increasingly common in infants and children. Accumulating evidence suggests that the ‘epidemic’ increase of childhood allergy may be associated with environmental factors such as stress. Although the impact of stress on the manifestation and exacerbation of allergy has been demonstrated, the underlying mechanisms of stress-induced exacerbation are still obscure. A growing number of studies have suggested an altered hypothalamus-pituitary-adrenal (HPA) axis function to stress in allergic children. It is speculated that a dysfunctional HPA axis in response to stress may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic sensitization and exacerbation especially under stressful conditions. In the present review the potential impact of a hyporesponsive as well as a hyperresponsive HPA axis on the onset and chronification of childhood allergy is summarized. Moreover, potential factors that may contribute to the development of an aberrant HPA axis responsiveness in allergy are discussed. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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.

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic–pituitary–adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.

Einleitung: Futterrationen für Hochleistungsmilchkühe basieren häufig auf Maissilage und liefern somit nur wenig frisches Gras, was eine niedrige Zufuhr an n-3-Fettsäuren, v.a. an α-Linolensäure (ALA), bewirkt. Dies führt einerseits zu einem reduzierten Status an ALA und konjugierter Linolsäure (CLA) und andererseits zu einem hohen n-6/n-3-Verhältnis bei laktierenden Kühen. Ziel der Untersuchungen: Das Ziel der vorliegenden Studie war es, die Einflüsse einer Supplementierung von essentiellen Fettsäuren (EFA, v.a. ALA) zusammen mit CLA auf den Fett- säurestatus, die Leistung, auf das antioxidative und inflammatorische System bei Milchkühen, die mit einer Mais-basierten Ration gefüttert wurden, in etablierter Laktation zu untersuchen und ver- schiede Stoffwechselwege, einschließlich der somatotropen Achse, näher zu beleuchten. Tiere, Material und Methoden: Es wurden 4 Kühe (3. Laktation, 126 ± 4 Tage in Milch) in einem 4 × 4 Latin Square untersucht. Die Kühe erhielten täglich abomasale Infusionen an Kokosöl (CTRL, 38,3 g/d; v.a. gesättigte Fettsäuren), Lein- und Distelöl (EFA, 39,1 und 1,6 g/d), Lutalin® (cis-9,trans-11 und trans-10,cis-12 CLA, jeweils 4,6 g/d) oder EFA+CLA für jeweils 6 Wochen. Die initiale Dosis wurde jeweils nach 2 Wochen verdoppelt, was in 3 Dosierungen resultierte (Dosis 1, 2 und 3). Es schloss sich eine 3-wöchige Washout-Periode an. Den Kühen wurde eine Mais-basierte Ration mit einem hohen n-6/n-3-V erhältnis (11,3:1) gefüttert. Die Trockensubstanzaufnahme und die Milchleistung wurden täglich und die Milchzusammensetzung wöchentlich gemessen. Die Fettsäuremuster im Milchfett und im Blutplasma, Plasmakonzentra- tionen von Metaboliten und Hormonen sowie von Parametern des antioxidativen Systems und der Immunantwort (nur in Woche 0 und 6) wurden jeweils in Behandlungswoche 0, 2, 4 und 6 analysiert. Lebergewebe wurde zu Beginn der Studie und jeweils nach 6 Wochen Behandlung entnommen und der Energiestoffwechsel sowie Parameter des antioxidativen Systems und der Immunantwort wurden auf Ebene der Transkription untersucht. Die statistische Auswertung wurde mittels ANOVA und der MIXED Prozedur (repeated measurements) in SAS durchgeführt, wobei Behandlung, Dosis und deren Interaktion als fixe Effekte und die Laktationswoche als Kovariable dienten. Ergebnisse: Die jeweils infundierten Fettsäuren stiegen sowohl im Plasma als auch in der Milch dosisabhängig an. Das n-6/n-3-Verhältnis des Milchfetts lag in der CTRL- und in der CLA- Gruppe höher als in den beiden EFA-Gruppen. Die Energie-korrigierte Milch und das Milchfett nahmen dosisabhängig in den beiden CLA-Gruppen ab. Es gab einen Trend für eine höhere Energiebilanz in der CLA-Gruppe. Der Milchproteingehalt war in den beiden CLA-Gruppen niedriger als in der CTRL-Gruppe und die Milchharnstoffkonzentration sank in beiden CLA- Gruppen dosisabhängig ab. Die Citratkonzentration in der Milch stieg dosisabhängig in der CLA- Gruppe an. Die Aktivität der Glutathionperoxidase im Blutplasma war in der CTRL-Gruppe ge- ringer als in der EFA-Gruppe und die Plasmakonzentration von β-Carotin stieg in beiden EFA- Gruppen mit der Dosis an. Die Plasmakonzentration des Gesamtcholesterols stieg dosisabhängig in allen Gruppen, außer der CLA-Gruppe, an. Die Plasmakonzentration des High-density- lipoprotein-Cholesterols stieg in der CTRL-Gruppe an und lag höher als in der EFA- und der CLA-Gruppe, während die Konzentrationen des Low-density-lipoprotein-Cholesterols dosisab- hängig in der EFA- und der EFA+CLA-Gruppe anstiegen und höher als in der CLA-Gruppe waren. Die hepatische Genexpression der 3-Hydroxy-3-methylglutaryl-CoA Synthase 1 wurde in allen Gruppen hochreguliert und lag in der EFA+CLA-Gruppe am höchsten. Die Genexpression des sterol regulatory element-binding factor 1 zeigte einen Trend für die niedrigsten Werte in den beiden EFA-Gruppen. Die Expression des leberspezifischen growth hormone receptor 1A (GHR1A) tendierte zu einer Erhöhung in der EFA+CLA-Gruppe im Vergleich zur CTRL-Gruppe. Die insulin-like growth factor I (IGF-I)-Plasmakonzentration stieg in der CLA-Gruppe an und der Plasmaspiegel des insulin-like growth factor binding protein 2 (IGFBP-2) lag in der EFA+CLA- Gruppe niedriger als in der CTRL-Gruppe. Die Albumin- und Harnstoffkonzentrationen im Plasma waren in der CLA-Gruppe niedriger als in der CTRL-Gruppe. Schlussfolgerungen: Die Milchfettdepression und das erhöhte Milch-Citrat weisen auf eine redu- zierte de-novo-Fettsäuresynthese und einen verbesserten oxidativen Status in der Milch durch CLA-Supplementierung hin. Weder CLA- noch EFA-Gaben zeigten eindeutige Wirkungen auf den Entzündungsstatus bei den Milchkühen. Die Supplementierung von EFA und CLA hatte Ein- fluss auf den Cholesterol- und den Fettstoffwechsel sowie deren Regulierung. Der erhöhte IGF- I-Plasma-Spiegel in der CLA-Gruppe sowie die niedrigere IGFBP-2-Plasmakonzentration und die erhöhte Genexpression des GHR1A in der Leber der EFA+CLA-Gruppe deuten auf stimulierende Effekte auf die somatotrope Achse hin. Weiterhin scheinen CLA-Gaben auch den Proteinstoffwechsel von Milchkühen zu beeinflussen.