Repeated Social Defeat Stress Induces HMGB1 Nuclear Export in Prefrontal Neurons, Leading to Social Avoidance in Mice

Abstract

Inflammation has been associated with depression, and innate immune receptors, such as the Toll-like receptor (TLR) 2/4 in the medial prefrontal cortex (mPFC), are crucial for chronic stress-induced depression-related behaviors in mice. HMGB1, a putative ligand for TLR2/4, has been suggested to promote depression-related behaviors under acute stress. However, the roles of endogenous HMGB1 under chronic stress remain to be investigated. Here, we found that the cerebroventricular infusion of HMGB1 proteins blocked stress-induced social avoidance and that HMGB1-neutralizing antibodies augmented repeated social defeat stress-induced social avoidance in mice, suggesting the antidepressive-like effect of HMGB1 in the brain. By contrast, the infusion of HMGB1-neutralizing antibodies to the mPFC and HMGB1 knockout in α-CaMKII-positive forebrain neurons attenuated the social avoidance, suggesting the pro-depressive-like effect of HMGB1 released from prefrontal neurons under chronic stress. In addition, repeated social defeat stress induced HMGB1 nuclear export selectively in mPFC neurons, which was abolished in the mice lacking RAGE, one of HMGB1 receptors, suggesting the positive feedback loop of HMGB1-RAGE signaling under chronic stress. These findings pave the way for identifying multiple roles of HMGB1 in the brain for chronic stress and depression.

Stress and the gut-brain axis: an inflammatory perspective

“…Most research performed in various stress models shows that functional changes (anxiety- and depressive-like behaviors) correlated with dysbiosis of the GBA, and IB disruption with an enhanced peripheral inflammatory response was associated with changes in BBB permeability and neuroinflammation. The impact of stress on GBA functions in the context of BBB changes is most commonly described in chronic stress paradigms (Liang et al, 2015 ; Bharwani et al, 2017 ; Nie et al, 2019 ; Yang et al, 2021 ; Jiang et al, 2023 ; Kitaoka et al, 2023 ), especially by employing social stressors (chronic social stress, or CUMS). CUMS-induced behavioral impairments were associated with the downregulation of intestinal TJs, upregulation of intestinal inflammatory factors followed by altered microbial diversity, and an increase in cortical and hippocampal microglia activation (Ait-Belgnaoui et al, 2014 ; He et al, 2024 ).…”

“NO” Time in Fear Response: Possible Implication of Nitric-Oxide-Related Mechanisms in PTSD

“…HMGB1 can act via activation of Toll-like receptor 4 (TLR4) or Receptor for Advanced Glycation End Product (RAGE) in microglia, resulting in the release of several inflammatory mediators [ 144 ]. In the brain, its levels can be increased by severe stress, contributing to neuroinflammation [ 145 , 146 ]. Patients exposed to trauma who then developed PTSD presented high levels of plasma HMGB1 when compared to those who did not develop the disorder [ 147 ], indicating that this DAMP could play a role in PTSD development.…”