Depression Mediated By Inflammatory Responses To Chronic Stress

Abstract

BackgroundMajor depressive disorder (MDD) is a chronic debilitating illness affecting yearly 350 million people worldwide. Although the mechanisms underlying depression are still not defined, it has been suggested that inflammation acts as depression mediator promoting glial and neuronal dysfunction. Microglia, as the resident innate immune cells of the brain, can be activated by both immune (i.e. infection) and nonimmune challenges (i.e. psychosocial stress), and contribute to the regulation of neurological and neuropsychiatric disorders. The aim of the present study is to characterize the inflammatory responses during chronic social stress and determine their effects on neuronal homeostasis and depression in a rodent depression model.MethodsThe Repeated Social Defeat Stress (RSDS) paradigm (10 days) was utilized to study the post RSDS stages [(10+5 days (D15) and 10+15 days (D25)] in 2–4 months old male C57BL/6J, CX3CR1‐GFP+ mice. At the beginning of the RSDS paradigm the mice were fed with chow containing the Csf1R inhibitors PLX5622 [passes blood brain barrier (BBB) and specifically targets microglia] or PLX73086 (does not cross BBB and targets peripheral monocytes) or control chow. In addition, all groups were administered BrdU (5‐bromo‐2’‐deoxyuridine) ad libitum to monitor cell proliferation. Behavioral tasks for social interaction, anxiety, anhedonia and despair behavioral (BH1 & BH2) were performed to categorize the defeated mice to susceptible (S; depressive‐like) and resilient (R; non‐depressive) to stress groups. The study focuses on the MDD‐affected Prefrontal (mPFC), Ventral or Lateral Orbital (VO/LO) Cortex areas. Cell quantification and data analysis were partially blinded and performed by 3 investigators.ResultsInflammation was observed in all areas at D15, depicted by the presence of activated Iba1+ cells [reactive morphology (CD68+) and inflammatory markers (TSPO, CD206, CD86, iNOS, Arg‐1)] in the S groups. Given the increased microglial numbers, microglial proliferation capacity was also examined after chronic stress, revealing a small increase in the S groups. Peripheral macrophage numbers (FACS; CD11b+CD45+high) were comparable at D15 in C, S and R groups. Remarkably, after microglial ablation (PLX5622), mice did not exhibit depressive behaviors, or altered cellular markers (c‐Fos, MAP2). This was altered after PLX withdrawal. Interestingly, PLX73086 chow also resulted in significant resilience to chronic stress, which was reversed to susceptibility after chow withdrawal, suggesting that PLX leaked into the CNS parenchyma, potentially a result of cerebrovascular compromise observed during chronic stress.ConclusionsOur data suggest that chronic stress induces microglial activation and recruitment, swiftly compromising neuronal homeostasis, leading to depressive‐like behavior in mice. Microglial elimination during psychosocial stress protected against the psychological and physical effects, pointing to the significance of microglia in modulating depression disorder.Support or Funding InformationThis work was supported by: American Heart Association #19PRE34370044 and Scholars in BioMedical Sciences Program T32GM127253.Graphical abstract of experimental outline.Figure 1