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Anxiety disorders are the most prevalent group of neuropsychiatric disorders and go along with high personal suffering. They often arise during childhood and show a progression across the life span, thus making this age a specific vulnerable period during development. Still most research about these disorders is done in adults. In light of this, it seems of utmost importance to identify predictive factors of anxiety disorders in children and adolescents. Temperament or personality traits have been proclaimed as risk markers for the development of subsequent anxiety disorders, but their exact interplay is not clear. In this dissertation an effort is made to contribute to the understanding of how risk markers of early temperamental traits, in this case Trait Anxiety, Anxiety Sensitivity and Separation Anxiety are interplaying. While Trait Anxiety is regarded as a more general tendency to react anxiously to threatening situations or stimuli (Unnewehr, Joormann, Schneider, & Margraf, 1992), Anxiety Sensitivity is the tendency to react with fear to one’s own anxious sensations (Allan et al., 2014; S. Reiss, Peterson, Gursky, & McNally, 1986), and Separation Anxiety is referring to the extent to which the child is avoiding certain situations because of the fear of being separated from primary care givers (In-Albon & Schneider, 2011). In addition, it will be addressed how these measurements are associated with negative life events, as well as brain functioning and if they are malleable by a prevention program in children and adolescents. In study 1 the aim was to extend the knowledge about the interrelations of this anxiety dimensions and negative life events. Results indicated positive correlations of all three anxiety traits as well as with negative life events. Thus, a close connection of all three anxiety measures as well as with negative life events could be indicated. The closest association was found between Anxiety Sensitivity and Trait Anxiety and between Separation Anxiety and Anxiety Sensitivity. Furthermore, negative life events functioned as mediator between Anxiety Sensitivity and Trait Anxiety, indicating that a part of the association was explained by negative life events. In study 2 we extended the findings from study 1 with neurobiological parameters and examined the influence of anxiety traits on emotional brain activation by administering the “emotional face matching task”. This task activated bilateral prefrontal regions as well as both hippocampi and the right amygdala. Further analyses indicated dimension-specific brain activations: Trait Anxiety was associated with a hyperactivation of the left inferior frontal gyrus (IFG) and Separation Anxiety with a lower activation bilaterally in the IFG and the right middle frontal gyrus (MFG). Furthermore, the association between Separation Anxiety and Anxiety Sensitivity was moderated by bi-hemispheric Separation-Anxiety-related IFG activation. Thus, we could identify distinct brain activation patterns for the anxiety dimensions (Trait Anxiety and Separation Anxiety) and their associations (Separation Anxiety and Anxiety Sensitivity). The aim of study 3 was to probe the selective malleability of the anxiety dimensions via a prevention program in an at-risk population. We could identify a reduction of all three anxiety traits from pre- to post-prevention-assessment and that this effect was significant in Anxiety Sensitivity and Trait Anxiety scores. Furthermore, we found that pre-intervention Separation Anxiety and Anxiety Sensitivity post-intervention were associated. In addition, pre-interventive scores were correlated with the intervention-induced change within the measure (i.e., the higher the score before the intervention the higher the prevention-induced change) and pre-intervention Anxiety Sensitivity correlated with the change in Separation Anxiety scores. All relations, seemed to be direct, as mediation/moderation analyses with negative life events did not reveal any significant effect. These results are very promising, because research about anxiety prevention in children and adolescents is still rare and our results are indicating that cognitive-behavioural-therapy based prevention is gilding significant results in an indicated sample even when samples sizes are small like in our study.
In sum the present findings hint towards distinct mechanisms underlying the three different anxiety dimensions on a phenomenological and neurobiological level, though they are highly overlapping (Higa-McMillan, Francis, Rith-Najarian, & Chorpita, 2016; Taylor, 1998). Furthermore, the closest associations were found between Anxiety Sensitivity and Trait Anxiety, as well as between Separation Anxiety and Anxiety Sensitivity. Specifically, we were able to find a neuronal manifestation of the association between Separation Anxiety and Anxiety Sensitivity (Separation Anxiety-specific IFG activation) and a predictive potential on prevention influence. The results of these studies lead to a better understanding of the etiology of anxiety disorders and the interplay between different anxiety-related temperamental traits and could lead to further valuable knowledge about the intervention as well as further prevention strategies.
Summary: I previously demonstrated that conditional overexpression of the neuronal nitric oxide synthase (nNOS) inhibited L-type Ca2+-channels and decreased myocardial contractility1 (Burkard N. et al. (2007). Circ Res 100, 32-44). However, nNOS has multiple targets within the cardiac myocyte and it is possible that interesting biological functions of this protein remain to be elucidated. In this study, I showed that nNOS overexpression has a cardioprotective effect after ischemia-reperfusion injury by inhibiting mitochondrial function and reducing the generation of reactive oxygen species (ROS). The effect of conditional nNOS overexpression in cardiac myocytes in ischemiareperfusion injury was assessed. Ischemia-reperfusion injury in WT mice resulted in nNOS accumulation in the mitochondria. Similary, transgenic nNOS overexpression caused nNOS abundance in mitochondria. Electron microscopy of mouse myocardium from nNOS overexpressing mice showed that after induction of its expression, nNOS is additionally localised in mitochondria. nNOS translocation into mitochondria was dependent on HSP90. Ischemia-reperfusion experiments in isolated hearts showed a cardioprotective effect of nNOS overexpression (30min post-ischemia, LVDP 27.0±2.5mmHg in non-induced animals vs. 45.2±1.9mmHg in nNOS overexpressing mice, n=12, p<0.05). Consistently with this finding, in vivo the infarct size within the area at risk was significantly decreased in nNOS overexpressing mice compared to non-induced animals (36.6±8.4 relative % vs. 61.1±2.9 relative %, n=12, p<0.05). nNOS overexpression also caused a significant increase in mitochondrial nitrite levels accompanied by a decrease of cytochrome c oxidase activity (72.0±8.9units/ml in nNOS overexpressing mice vs. 113.2±17.1units/ml in non-induced mice, n=12, p<0.01) resulting in an inhibition of mitochondrial function. Accordingly, O2-consumption (MVO2) in isolated heart muscle stripes was decreased in nNOS overexpressing mice, already under resting conditions (0.016±0.0015 vs. 0.024±0.006ml[O2] x mm-3 x min-1, n=13, p<0.05). Additionally, this study showed that the ROS concentration was significantlydecreased in hearts of nNOS overexpressing mice compared to non-induced animals (6.14±0.685 vs. 14.53±1.7μM, n=8, p<0.01). Application of different inhibitors, Western Blot analysis and activity assays showed that the lower ROS concentration in nNOS overexpressing mice was caused by inhibition of the xanthine oxidoreductase (XOR) activity by the increased abundance of nNOS expression. In summary, this study demonstrated that the conditional transgenic overexpression of nNOS resulted in myocardial protection after ischemia-reperfusion injury. Besides reduction of myocardial Ca2+-overload after reperfusion this might be caused by inhibition of mitochondrial function through nNOS, which reduced myocardial oxygen consumption already under baseline conditions (Burkard N. conditionally accepted by