Neuroimmunological processes in rodent models of inflammation- associated depressive disorders

Summary excerpts: Clinical depression is a heterogeneous disorder with unknown etiology. Although the exact pathogenesis is still unclear, most experts in the field agree that depression is caused by a complex interaction between genetic and environmental factors. Several lines of evidence indicate that inflammatory processes may also be involved in the development of depression, at least in subsets of vulnerable individuals. For instance, depression frequently occurs as a comorbidity of medical conditions characterized by chronic inflammatory processes. Even in absence of other medical illness, many depressed patients display marked alterations in inflammatory cytokine levels and immune cell activity. Moreover, therapeutic administration of proinflammatory cytokines is able to elicit depression in psychiatric healthy subjects. The fact that these cytokines are typically administered intravenously indicates that activation of the immune system in the periphery has profound effects on the brain. Validated animal models are needed to elucidate the biological underpinnings of inflammation-associated depression and to screen for novel drugs. Despite extensive scientific research during the past decades, no such animal models are currently available. Several groups have proposed that peripheral immune activation using stimuli such as LPS or proinflammatory cytokines can be used to model inflammation-associated depression in rodents. It is suggested that these immune stimuli elicit a biphasic response in which an initial episode of sickness is followed by a depressive-like phenotype. However, the use of different experimental approaches and reports of contrasting results makes it difficult to interpret currently available literature. In this study, a combination of techniques and readouts was used to investigate the time course of central effects induced by peripheral immune stimuli. The main immune stimulus used throughout the study is LPS, an immunostimulant that mimics the early phases of a bacterial infection. Although fairly high doses of LPS have been used, it is shown that humans are about 100,000-fold more sensitive to LPS than rodents [282]. Moreover, the fact that even a low dose of LPS was found to have mood altering effects in humans [283, 284] supports the idea that LPS injection in mice is a suitable model to study the molecular mechanisms of inflammation-associated behavioral changes. .... To summarize, the results of this thesis confirm that peripheral immune activation elicits a robust neuroinflammatory response that is accompanied by behavioral alterations. It is becoming clear that these processes are a doubleedged sword. Where at first inflammation activates pathways that are neuroprotective and needed to restore homeostasis, overstimulation of these pathways can induce a depressive phenotype. Further research on the molecular mechanisms of inflammation-associated depression can therefore contribute to the identification of disease-specific biomarkers and lead to the discovery of novel therapeutical strategies to treat certain subtypes of depression.

Publication year:2014

Accessibility:Open