Interactions between peripheral monocytes and the neurovasculature as a pathomechanism of depression - a translational study

  • Cathomas, Flurin (PI)

Project Details

Description

Major depressive disorder (MDD) is a complex neuropsychiatric syndrome with a significant impact on individual burden and global health. Psychosocial stress is one of its most important risk factors. Both pre-clinical animal models and human studies have shown that psychosocial stress can lead to chronic low-grade inflammation, and a subset of MDD patients show elevated inflammatory mediators, such as pro-inflammatory cytokines. Recent evidence from the laboratory of Prof. Scott Russo suggests that, in an animal model of chronic social defeat stress, stress susceptible mice show brain region specific disruption of the neurovasculature, leading to an increased permeability for cytokines and potentially leukocytes. Additionally, results obtained during my Early Postdoc.Mobility fellowship indicate that stress in susceptible but not resilient mice leads to an increased expression of several genes that are involved in monocyte-endothelial cell interactions.Based on these findings, I propose an extension of my fellowship, which will allow me to complement my previous research findings on the role of inflammation and social stress as pathomechanism for depression-relevant behaviors in mice and humans. The overall aim of the proposed translational study is to identify immune-endothelial interactions and test causal mechanisms related to neurovascular damage and the active recruitment of peripheral immune cells to mood-related brain structures controlling depression-like behaviors. I hypothesize that stress increases the potential of monocytes to interact with endothelial cells of the neurovasculature, leading to increased-stress susceptibility through induction of vascular damage and monocyte infiltration into the perivascular space. Secondly, I hypothesize that stress results in region specific differences in gene and protein expression of endothelial cells responsible for the attraction of monocytes. To test these hypotheses, I will use a translational approach: In a mouse model of social defeat stress, I will functionally investigate the role of stress induced increased expression of chemokine receptors on leukocytes using bone marrow chimeras. I will further investigate cell-type specific transcriptional signatures of endothelial cells in the limbic system and based on these data manipulate endothelial gene expression using viral-vector mediated manipulation of endothelial cells. Complementary to the pre-clinical mouse studies, I will perform a detailed characterization of leukocyte subtypes in MDD patients and healthy controls using cell-type specific RNA-sequencing and mass cytometry. This project will provide important insights into the pathophysiology of stress related neuropsychiatric disorders. Given that there is increasing evidence for an inflammatory component to mental illnesses, the current study has the potential to reveal mechanisms that apply to several other neuropsychiatric disorders and could inform the future development of novel treatment options.

StatusFinished
Effective start/end date1/08/1931/01/21

Funding

  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

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