Stress increases blood beta‐hydroxybutyrate levels and prefrontal cortex NLRP3 activity jointly in a rodent model

Aim This study aimed to assess the response of endogenous beta‐hydroxybutyrate to psychological stress, and its association with nucleotide‐binding domain, leucine‐rich repeat, pyrin domain‐containing 3 (NLRP3) inflammasome, and stress‐induced behavior. Methods Male C57BL/6J mice were subjected to 1‐hour restraint stress to examine changes in the endogenous beta‐hydroxybutyrate and active NLRP3 levels in the prefrontal cortex. Subsequently, we created a depression model applying 10‐day social defeat stress to the male C57BL/6J mice. Results One‐hour restraint stress rapidly increased beta‐hydroxybutyrate levels in the blood. The active NLRP3 levels in the prefrontal cortex also increased significantly. A correlation was found between the increased beta‐hydroxybutyrate levels in the blood and the active NLRP3 levels in the prefrontal cortex. The mice exposed to social defeat stress exhibited depression‐ and anxiety‐like behavioral changes in the open field, social interaction, and forced swim tests. There was a correlation between these behavioral changes and endogenous beta‐hydroxybutyrate levels. Among the social defeat model mice, those with high beta‐hydroxybutyrate levels tended to have more depression‐ and anxiety‐like behavior. Conclusions The increased blood beta‐hydroxybutyrate levels due to psychological stress correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that the increased beta‐hydroxybutyrate levels due to stress may reflect a reaction to brain inflammation. In addition, mice with higher blood beta‐hydroxybutyrate levels tend to exhibit increased depression‐ and anxiety‐like behaviors; thus, an increase in blood beta‐hydroxybutyrate levels due to stress may indicate stress vulnerability. Psychological stress increased blood beta‐hydroxybutyrate (BHB) levels. Mice with higher blood BHB levels tend to exhibit increased depression‐ and anxiety‐like behaviors. The increased blood BHB levels correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that increased blood BHB levels may represent stress vulnerability.