Abstract
The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) 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 NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB 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 NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB 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 NFκB 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 NFκB activity. These results highlight the inhibitory action of GR on NFκB 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.
Highlights
A growing body of evidence suggests that inflammation has a pathophysiological role in depression
During the monitoring of nuclear factor-κ-B (NFκB) activity by bioluminescent signal image (BLI), we noticed that the reporter was insufficient for monitoring NFκB activation in the ILPFC or the dermis (Fig. 1a, b)
The monitoring of NFκB activity with this improved reporter showed clear dermal NFκB activation at 2 h post-LPS; there was still no NFκB activation observed in the IL-PFC (Fig. 1c), which may be an in vivo evidence for different responses of NFκB in the IL-PFC and dermis
Summary
A growing body of evidence suggests that inflammation has a pathophysiological role in depression. Transgenic reporter mice are an alternative solution to the direct monitoring of biological processes [6, 7], in vivo real-time monitoring of their activation has been inaccessible, partly due to the difficulty in spatial resolution, that could describe such events Their clonal ubiquity leads to poor special resolution and severely impedes pinpoint monitoring of transcriptional activity. Spacious bioluminescence is a major disadvantage in studying anatomical brain function in which those functions can be attributed to different regions of the brain or even the same cell type [8, 9] Other strategies, such as Cre-Lox recombination [10] and the non-viral gene delivery system [11], have unresolved problems with bioluminescence. Understanding the NFκB-GR interplay during the behavioral outcomes helps to decipher the molecular mechanisms underlying the etiology of inflammationassociated depression
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