Decoding the temporal nature of brain GR activity in the NFκB 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-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.

Network and Experimental Pharmacology to Decode the Action of Wendan Decoction Against Generalized Anxiety Disorder

“…Persistent chronic stress abnormally activates the HPA axis, which is an important factor in the development of chronic inflammatory responses and anxiety. [50][51][52][53] Repeated restraint stress (RRS) model is established by imposing sustained stress response on animals through long-term restraint typically used to stimulate GAD that is accompanied by hypercortisolism and anxiety-like behaviors. 54 In the present study, we established a mouse model of RRS based on previous literature and found that RRS models spent shorter dwell times in the central zones (open field test) and in the open arms (EPM test) than normal mice, as well as exhibited a significant increase in serum corticosterone.…”

Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link

“…Upon activation the p65:p50 dimer translocate to the nucleus where it binds specific DNA sequences called κB response elements and induce transactivation of target genes (Giridharan & Srinivasan, 2018). In-vivo tracking of activated p65 showed that the expression of κB responsive genes were significantly higher in animals that were challenged during the resting period (GC low) than during the active period (GC high) supporting the circadian influence on NF-κB p65 activation (Han et al, 2021). The profound anti-inflammatory effects of GC are largely attributed to GR mediated inhibition of NF-κB p65, by one of three methods.…”

“…Age related changes in circulating cortisol have been variably reported in humans, with many studies suggesting higher plasma cortisol concentrations in older individuals ( Echouffo-Tcheugui et al, 2018 ; Hatfeld et al, 2004 ; Pietrzak et al, 2017 ). The discrepancies in observations could be attributed to the methods of assessment and the number and frequency of samples assessed.…”

Neutrophil modulation of behavior and cognition in health and disease: The unexplored role of an innate immune cell

“…Interleukin 1β (IL‐1β) increased in the brain of mice when exposed to a startle stimulus 45 . Peripheral administration of the same cytokine attenuated the startle response through its activity on the adrenal gland leading to the release of glucocorticoids, which have anti‐inflammatory properties 46,47 . Indeed, the startle response led to an increase in corticosterone expression in rats 48 .…”