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Disruptions of extinction learning mechanisms are thought to be involved in the aetiology of several mood- and anxiety related mental disorders. We test the hypothesis that interindividual variation in extinction learning processes is partly attributable to the genetic make-up, which might be associated with mental health risk through effects on extinction learning. Genetic variants may impact the structural and functional connectivity of the extinction network such that genetically driven alterations of network properties give in part rise to the observed individual rates of learning. Hence, we aim to assess the extent to which genetic predisposition for mental disorders are associated with physiological measures of fear learning during acquisition and extinction. Additionally, we investigate whether this association is mediated by structural and connectivity patterns in key regions within the extinction network.

Habilitation, Universität Duisburg-Essen, 2011

Dysfunction of the central dopaminergic system is associated with neurodegenerative disorders and mental illnesses such as Parkinson's disease and schizophrenia. Patients suffering from these diseases were reported to exhibit altered immune functions compared to healthy subjects and imbalance of the central dopaminergic system has been suggested as one causative factor for the immune disturbances. However, it is unclear whether the observed immune changes are primary or secondary to the disease. Here we demonstrate that central dopamine (DA) depletion in a rat model of Parkinson's disease induced transient changes in blood leukocyte distribution and cytokine production that were apparent until four weeks after bilateral intrastriatal administration of the neurotoxin 6-hydroxydopamine (6-OHDA). Eight weeks after treatment, no differences in blood immune parameters were anymore evident between neurotoxin-treated and control animals. Nevertheless, animals with a widespread damage of dopaminergic neurons in the nigrostriatal system showed an exacerbated pro-inflammatory response following in vivo challenge with bacterial lipopolysaccharide. Our data indicate that peripheral immune perturbations in the early phase after intrastriatal 6-OHDA administration might have been related to the neurodegenerative process itself whereas the increased sensitivity to the inflammatory stimulus seems to have resulted from an impaired dopaminergic control of prolactin (PRL) and corticosterone (CORT) secretion. The findings demonstrate that the brain dopaminergic system is involved in peripheral immune regulation and suggest that central dopaminergic hypoactivity bears the risk of excessive inflammation, e.g., during infection or tissue injury.

Pavlovian conditioning is one of the major neurobiological mechanisms of placebo effects, potentially influencing the course of specific diseases and the response to a pharmacological therapy, such as immunosuppression. In our study with behaviorally conditioned rats, a relevant taste (0.2% saccharin) preceded the application of the immunosuppressive drug cyclosporin A (CsA), a specific calcineurin (CaN) inhibitor. Our results demonstrate that through pavlovian conditioning the particular pharmacological properties of CsA can be transferred to a neutral taste, i.e., CaN activity was inhibited in splenocytes from conditioned rats after reexposure to the gustatory stimulus. Concomitant immune consequences were observed on ex vivo mitogenic challenge (anti-CD3). Particularly, Th1-cytokine, but not Th2-cytokine, production and cell proliferation were impeded. Appropriate pharmacological and behavioral controls certify that all these changes in T-lymphocyte reactivity are attributable to mere taste reexposure. Furthermore, the underlying sympathetic-lymphocyte interaction was revealed modeling the conditioned response in vitro. CaN activity in CD4(+) T lymphocytes is reduced by beta-adrenergic stimulation (terbutaline), with these effects antagonized by the beta-adrenoreceptor antagonist nadolol. In summary, CaN was identified as the intracellular target for inducing conditioned immunosuppression by CsA, contributing to our understanding of the intracellular mechanisms behind "learned placebo effects."

In der vorliegenden Arbeit wurde die Rolle des sympathischen Nervensystems (SNS) im Verlauf einer Friend Retrovirus (FV)-Infektion bei Mäusen untersucht. Es konnte gezeigt werden, dass es zum Höhepunkt der virus-induzierten Splenomegalie zu einem massiven Verlust des sympathischen Neurotransmitters Noradrenalin (NA) in der Milz kommt. Dieser Effekt war transient und am Ende der akuten Infektion nicht mehr zu beobachten. Die FV-induzierte NA-Depletion konnte durch die pharmakologische Blockade der Katecholamin-degradierenden Enzyme Monoaminoxidase A (MAO-A) bzw. Catechol-O-Methyltransferase (COMT) mithilfe der selektiven Inhibitoren Clorgylin bzw. 3,5-Dinitrocatechol verhindert werden. Diese Intervention führte in FV-infizierten Mäusen zudem zu einer signifikanten Reduktion in der Viruslast und zu einer verminderten virus-induzierten Splenomegalie. Eine periphere chemische Sympathektomie vor der FV-Infektion hatte hingegen eine verstärkte Pathologie zur Folge. Sympathektomierte FV-infizierte Mäuse wiesen im Vergleich zu intakten Tieren eine signifikant höhere Viruslast auf und zeigten eine signifikant stärkere Splenomegalie. Eine Behandlung mit selektiven adrenergen Agonisten bzw. Antagonisten hatte keinen Einfluss auf den Infektionsverlauf. In chronisch FV-infizierten Tieren führte die chemische Sympathektomie ebenfalls zu einer Vergrößerung der Milz. Direkte Effekte von NA auf die Virus-Replikation konnten in in vitro Experimenten ausgeschlossen werden. Die Expression von β-adrenergen Rezeptoren in Erythrozyten-Vorläuferzellen deuten auf eine mögliche Interaktion des Neurotransmitters mit den Zielzellen des Virus hin, was jedoch in weiterführenden Experimenten bestätigt werden muss. Zusammengefasst zeigen die Ergebnisse dieser Arbeit, dass es während der Pathogenese einer FV-Infektion zu Veränderungen im Neurotransmitterstoffwechsel in einem wichtigen Zielorgan der Infektion kommt. Pharmakologische Interventionen, die eine experimentelle Erhöhung bzw. Erniedrigung der NA-Konzentration in der Milz bewirken, haben eine abgeschwächte bzw. verstärkte Pathologie zur Folge. Des Weiteren demonstriert diese Arbeit, als eine von wenigen präklinischen Studien, dass sich das SNS, während einer retroviralen Infektion, für den Wirt als äußerst vorteilhaft erweisen kann. Somit wird deutlich, dass ein dringender Bedarf an klinischen Studien besteht, die das Risiko und das therapeutische Potential von adrenergen Agonisten/Anatgonisten oder von MAO-A/COMT-Inhibitoren in Patienten retroviraler Infektionserkrankungen, sorgfältig beurteilen. The present thesis investigated the role of the sympathetic nervous system (SNS) during Friend retrovirus (FV) infection in mice. Results show that the splenic concentration of the sympathetic neurotransmitter noradrenaline (NA) was massively reduced at the peak of the virus-induced splenomegaly. This effect was transient and could not be observed at the end of the acute infection. FV-induced NA depletion was prevented by pharmacological inhibition of the catecholamine degrading enzymes monoamine oxidase A (MAO-A) and catechol-O-methyltransferase (COMT) using the selective inhibitors clorgyline (CLG) and 3,5-dinitrocatechol (OR-486). Moreover, this intervention resulted in significantly reduced viral load and a less pronounced virus-induced splenomegaly in FV-infected mice. In contrast, chemical sympathectomy prior to FV-infection aggravated the pathology of the disease. Sympathectomized and simultaneously FV-infected mice exhibited both, a significant higher viral burden and a more pronounced increased splenomegaly compared to intact FV-infected mice. Noteworthy, treatment with selective adrenergic agonists or antagonists did not influence the course of FV infection. Chemical sympathectomy in chronically FV-infected mice also resulted in a significant enlargement of the spleen. Direct effects of NA on viral replication could be excluded by in vitro studies. The expression of β-adrenergic receptors in erythroid precursor cells suggests a possible interaction between the sympathetic neurotransmitter and the viral target cells. However, this has to be confirmed in future experiments. Together, the results of this thesis demonstrate that FV infection leads to substantial changes in neurotransmitter metabolism in the spleen, one of the main sites of viral replication. Pharmacological interventions, that increase or decrease splenic NA concentration, can have a major impact on viral pathology. Furthermore, this work belongs to the minority of pre-clinical studies that were able to demonstrate, that the SNS plays an important and beneficial role for the host in terms of retroviral infections. Thus, there is an urgent need for clinical studies that carefully evaluate the risks and therapeutic potential of adrenergic agonists/antagonists or MAO-A/COMT inhibitors in patients suffering from retroviral infections.