Social hierarchy and resilience affect stress-induced PTSD via Uba7 gene expression and subsequent inflammation in microglia of the mPFC.

Abstract

Post-traumatic stress disorder (PTSD) occurs in individuals who have experienced a traumatic event; however, not everyone who has experienced a traumatic event will develop this condition, highlighting the significance of susceptibility factors. Social hierarchy is a critical behavioral regulator of stress susceptibility and a risk factor for mental disorders. Individual resilience, the ability to recover from acute stress and preclinical injury, also plays a role in PTSD susceptibility. Some studies found that individuals with higher social rank were more resilient. Furthermore, individuals of a lower social rank exhibit increased microglial activity and the release of pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α); however, their exact role in PTSD remains unclear. Research has indicated that the nuclear factor kappa B (NF-κB) signaling pathway in the medial prefrontal cortex (mPFC) was activated abnormally in PTSD and correlated with changes in ubiquitin-like modifier activating enzyme 7 (Uba7) gene expression. However, the specific roles of Uba7 and the NF-κB pathway in PTSD susceptibility necessitate further investigation. Understanding these factors is crucial for comprehending the psychopathological changes in PTSD and developing preventive strategies. Our study validated three PTSD phenotypes using the mouse single prolonged stress (SPS) model, finding that resilience influenced PTSD recovery over time. Subsequently, we employed the chronic social defeat stress (CSDS) model to evaluate differential stress responses and recovery patterns over 14 days in mice of various social hierarchies and examined the related molecular changes in their mPFC. The results indicated that social hierarchy predicted PTSD susceptibility, with dominant individuals exhibiting greater vulnerability and more severe initial symptoms. Over time, resilient individuals in the lower-ranked groups recovered faster from anxiety and depression than those in the higher-ranked groups. Overactivation of microglia in the mPFC of susceptible individuals was associated with increased expression of NF-κB p65 and signals transducer and activator of transcription (STAT1) proteins, Uba7 gene expression, and TNF-α. Our findings highlight the complex interplay between social status and PTSD risk factors.