Recovery after stress on HPA activity, memory and associated molecular changes in LPS-challenged rats.

Abstract

The long-term impact of chronic stress and immune activation on hypothalamic-pituitary-adrenal (HPA) axis function, cognition, neuroinflammation, oxidative stress, and neuroprotective proteins like FOXO3 and CDK10 remains poorly understood, especially in the context of post-stress recovery followed by acute immune challenge. Therefore, this study aimed to investigate the effects of a recovery period following chronic unpredictable mild stress (CUMS) on HPA axis function, memory performance, oxidative stress, neuroinflammation, and the concentration of FOXO3 and CDK10 in lipopolysaccharide (LPS)-challenged rats. 12-week-old male Sprague-Dawley rats were randomly divided into five groups (n=5/group): Control, CUMS, PSR, LPS, and PSR+LPS. After a week of acclimatisation, a 10-day CUMS protocol was applied, and a 7-day recovery period. Thereafter, rats received a single dose of LPS (5 mg/kg, i.p.). After LPS injection, Spatial learning and memory were evaluated with a Morris-Water Maze Test. Blood, hippocampus, and cerebral cortex were then collected for biochemical analyses such as ELISA and RT-qPCR. These biochemical analyses were used to quantify specific proteins and assess gene expression levels. CUMS elevated CRH, ACTH, and corticosterone concentration, indicating sustained HPA axis activation. LPS increased corticosterone and GR levels, reflecting a compensatory neuroendocrine response. Importantly, the PSR+LPS group demonstrated an adaptive HPA axis profile, marked by increased GR and reduced ACTH and corticosterone in specific brain regions. Recovery following stress partially improved memory performance and reduced neuroinflammation, as indicated by increased time spent in the goal quadrant and lower IL-1β concentration. However, oxidative stress persisted as evidenced by an increase in the CUMS and LPS groups, and FOXO3 and CDK10 concentrations were only partially restored. Overall, these findings suggest that recovery may promote partial neuroendocrine adaptation to subsequent immune challenges, although residual oxidative and inflammatory disturbances persist.