Decoding the temporal nature of brain GR activity in the NF kappa B signal transition leading to depressive-like behavior

Abstract

The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-kappa-B (NF kappa B) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NF kappa B in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NF kappa B and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NF kappa B activity established a behavioral basis for the NF kappa B signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NF kappa B signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NF kappa B in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NF kappa B signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NF kappa B activity. These results highlight the inhibitory action of GR on NF kappa B by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.