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Studying the effects of increased tumor necrosis factor (TNF) in periphery versus specific brain regions on depression-relevant behavior and physiological markers in mice


Klaus, Federica. Studying the effects of increased tumor necrosis factor (TNF) in periphery versus specific brain regions on depression-relevant behavior and physiological markers in mice. 2015, University of Zurich, Faculty of Science.

Abstract

Depression is a heterogeneous mental illness with symptoms including sadness, helplessness, anhedonia, fatigue and suicidality. Based on its increasing prevalence, depression is predicted to be the second major cause of disability worldwide by 2020. Despite this fact, the aetio-pathophysiology of depression remains poorly understood. Human clinical and experimental studies have linked the inflammatory cytokine network with depressive symptoms, leading to the cytokine hypothesis of depression. However, the direction of the causal relationship between depression and the activation of the immune system, as well as the involved mediators and pathways, have not yet been clarified. Valid translational animal models are essential to investigate the hypothesis postulating that peripheral and central immune-activation, especially increased TNF, is induced by stress and effects neurobiological changes leading to depression. Several studies in rodents have investigated the effects of a single TNF application on behavior, but not of a prolonged TNF increase, although this would correspond more closely to the low, prolonged increase in plasma TNF observed in human depression. This PhD project provides insight into the differential effects of a prolonged increase of TNF in the periphery versus specific brain regions on behaviors that can be translated to symptoms or domains of depression. The main focus was placed on the reactivity to negative stimuli, as assessed by fear conditioning-expression and avoid-escape behavior, and on the reactivity to positive stimuli, as assessed by saccharin versus water consumption and preference. Repeated injection as well as continuous delivery of TNF in the periphery were investigated, and chronic elevation of TNF expression in specific brain regions, namely periventricular regions, amygdala and hippocampus were achieved using viral vectors. This project demonstrated in mice that peripheral increases in TNF resulted in moderate sickness, an increased reactivity to negative stimuli and a reduced reactivity to reward, effects that co-occurred with splenomegaly and increases in plasma IL-B6 and IL-B10 while not leading to glial activation. Central increase in TNF led to increased reactivity to negative stimuli when localized to periventricular regions of hippocampus, while increased amygdala TNF led to reduced reactivity to saccharin and did so in the absence of both sickness in terms of body weight loss and changes in the plasma levels of cytokines. These findings provide important new insights into the causal inter-relationships between peripheral TNF, central TNF and depression-relevant behavior and will inform research and development relevant to anti-inflammatory strategies of antidepressant treatment.

Abstract

Depression is a heterogeneous mental illness with symptoms including sadness, helplessness, anhedonia, fatigue and suicidality. Based on its increasing prevalence, depression is predicted to be the second major cause of disability worldwide by 2020. Despite this fact, the aetio-pathophysiology of depression remains poorly understood. Human clinical and experimental studies have linked the inflammatory cytokine network with depressive symptoms, leading to the cytokine hypothesis of depression. However, the direction of the causal relationship between depression and the activation of the immune system, as well as the involved mediators and pathways, have not yet been clarified. Valid translational animal models are essential to investigate the hypothesis postulating that peripheral and central immune-activation, especially increased TNF, is induced by stress and effects neurobiological changes leading to depression. Several studies in rodents have investigated the effects of a single TNF application on behavior, but not of a prolonged TNF increase, although this would correspond more closely to the low, prolonged increase in plasma TNF observed in human depression. This PhD project provides insight into the differential effects of a prolonged increase of TNF in the periphery versus specific brain regions on behaviors that can be translated to symptoms or domains of depression. The main focus was placed on the reactivity to negative stimuli, as assessed by fear conditioning-expression and avoid-escape behavior, and on the reactivity to positive stimuli, as assessed by saccharin versus water consumption and preference. Repeated injection as well as continuous delivery of TNF in the periphery were investigated, and chronic elevation of TNF expression in specific brain regions, namely periventricular regions, amygdala and hippocampus were achieved using viral vectors. This project demonstrated in mice that peripheral increases in TNF resulted in moderate sickness, an increased reactivity to negative stimuli and a reduced reactivity to reward, effects that co-occurred with splenomegaly and increases in plasma IL-B6 and IL-B10 while not leading to glial activation. Central increase in TNF led to increased reactivity to negative stimuli when localized to periventricular regions of hippocampus, while increased amygdala TNF led to reduced reactivity to saccharin and did so in the absence of both sickness in terms of body weight loss and changes in the plasma levels of cytokines. These findings provide important new insights into the causal inter-relationships between peripheral TNF, central TNF and depression-relevant behavior and will inform research and development relevant to anti-inflammatory strategies of antidepressant treatment.

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Additional indexing

Item Type:Dissertation
Referees:Pryce Christopher, Dantzer Robert
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:October 2015
Deposited On:20 Jan 2016 14:54
Last Modified:05 Apr 2016 19:58
Number of Pages:136
Funders:Swiss National Science Foundation

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