Chronic Stress Induces Inflammatory Responses and Compromises the NG2‐Glial Homeostasis during Depression
Authors: Kokkosis Alexandros , Mullahy Matthew , Aguirre Adan , Tsirka Styliani‐Anna (Stella) 
Published: June 2021

Background & Objective

Major depressive disorder (MDD) is a chronic debilitating illness affecting yearly 350 million people worldwide. Although the underlying mechanisms of depression are still not well defined, it has been suggested that psychosocial and oxidative stressors act as depression mediators of inflammatory responses and promote neuronal and glial malfunctions. We have recently established an important association of oligodendrocyte progenitor cells (NG2‐glia) with depression‐like behavior in an adult murine depression model of chronic stress (repeated social defeat stress, RSDS). The aim of the present study is the time‐dependent characterization of the RSDS‐induced inflammatory responses on the NG2‐glial homeostasis.

Methods

The RSDS paradigm (10 days) was utilized to characterize the NG2‐glial dynamics during the early (5 days) and post RSDS stages (10+2 days and 10+15 days) in 8–12 weeks old male C57BL/6J and CSPG4‐EGFP+ mice. Throughout the RSDS, groups were given access ad libitum to BrdU (5‐bromo‐2′‐deoxyuridine) in drinking water to monitor cell proliferation. Social interaction test (SI) and several behavioral tests (BH) were performed at the end of the paradigm to categorize the defeated mice to susceptible (S) and resilient (R) mice. Mice were then euthanized, and brains were isolated to study the MDD‐affected area of Prefrontal Cortex (PFC; n=4–6/per group). Data analysis was blinded and performed by 2 different investigators in each experiment. For the morphology analyses 6–8 traced cells per mouse were analyzed by Neurolucida software.

Results

Inflammatory responses were observed in the PFC area, as depicted by the microglial recruitment (Iba1), activation (reactive morphology) and inflammatory markers during the RSDS in the S groups. A time‐dependent decrease of NG2‐glial density (PDGFRα marker and CSPG4‐EGFP+ reporter line) was observed in the PFC in S groups. Given the highly proliferative profiles of NG2 glia in adult CNS, the mitotic capacity (BrdU and Ki67) was examined during chronic stress. Time‐dependent alterations in proliferation capacity were evident in the S groups. In addition, BrdU labeling retention revealed the NG2‐glial fate and responses in this model of chronic stress. Remarkably, in the S groups increased NG2‐glial differentiation was observed towards oligodendrocytes (GST‐pi) in the early RSDS stages, and a concomitant switch towards NG2‐glial production in the post RSDS stages. In addition, chronic stress also induced alterations in the NG2‐glial morphology and branching in the S groups, which are crucial features of NG2‐glial proliferation and communication with the rest of glia and neurons.

Conclusions

Chronic stress induces inflammatory responses mediated by microglial activation and recruitment, and NG2‐glial cellular homeostasis is swiftly compromised leading to time‐dependent alterations of proliferation, viability and progeny contributing to the onset of depressive‐like behavior in mice.

Support or Funding Information

This work was supported by: ‐ AMERICAN HEART ASSOCIATION GRANT # 19PRE34370044/2019 ‐ R01 RMH099384A(AA) ‐ Scholars in BioMedical Sciences Program (AGK)

Graphic outline of experiments.

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Graphic outline of experiments.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.