Chronic mild stress leads to anxiety-like behavior and decreased p70 S6K1 activity in the hippocampus of male mice

• Published in: Physiology & behavior 2024-01, Vol.273, p.114377-114377, Article 114377
• Main Authors: David, Jazmine, Mousset, Marike, Trombetti, Kirby, Sayasouk, Beverly, Neilsen, Calvin, Suorsa, Parker, Ruben, Melissa, Ruben, Elias, Thiessen, Jacob, Pychewicz, Taylor, Chu, Ping, Huynh, Thu N.
• Format: Article
• Language: English
• Subjects: adults; Anxiety; behavior; Chronic mild stress; glycogen (starch) synthase; Hippocampus; males; Mice; mTORC1; non-specific serine/threonine protein kinase; p70 S6K1; pathogenesis; phosphorylation; rapamycin; ribosomal proteins; tubulin; Western blotting
• ISSN: 0031-9384; 1873-507X
• DOI: 10.1016/j.physbeh.2023.114377

•Chronic mild stress leads to anxiety-like behavior in the open field and elevated plus maze.•Chronic mild stress results in a reduction in p70 S6K1 activity and GSK3β phosphorylation in the hippocampus of male mice.•Pharmacological inhibition of p70 S6K1 in male wildtype mice results in anxiety-like behavior in the open field and elevated plus maze. Major affective disorders are highly prevalent, however, current treatments are limited in their effectiveness due to a lack of understanding of underlying molecular mechanisms. Recent studies have shown that reduced activity of p70 S6 kinase 1 (S6K1), a downstream target of the mechanistic target of rapamycin complex 1 (mTORC1), is linked to anxiety-like behavior in both humans and rodents. The purpose of this study was to investigate the relationship between S6K1 and anxiety-like behavior following chronic mild stress (CMS) and drug-induced inhibition of S6K1. Following CMS, anxiety-like behavior was evaluated using an open field (OF) and elevated plus maze (EPM) in adult male C57/Bl6 mice. After behavior analysis, samples of the hippocampus were harvested for quantification of S6K1, S6 ribosomal protein, glycogen synthase kinase-3 β (GSK3β), and beta tubulin via western blot. Our results demonstrate that CMS mice exhibit anxiety-like behavior in the OF and EPM and reduced activity of S6K1 in the hippocampus (HPC). We measured phosphorylation levels of GSK3β and found that GSK3β phosphorylation was also reduced following CMS compared to control mice. Furthermore, pharmacological inhibition of S6K1 with PF-4708671 in male mice was sufficient to produce anxiety-like behavior in the OF and EPM. These results further support the significant role of S6K1 in the pathogenesis of anxiety and affective disorders.