Octanoic acid treatment alleviates cold-induced depression-like behaviors via targeting the AKR1B1-PGF2α pathway

Environmental factors play a crucial role in the onset and progression of negative mood. Low temperature, an important environmental factor, acutely induces negative mood and increases depression risk. However, mechanisms underlying low temperature-induced negative mood and its prevention remain unclear. Here, we report acute cold exposure-induced depression-like behaviors in a mouse model; these behaviors were alleviated under prolonged cold exposure. Plasma-targeted fatty acid analysis revealed a significant correlation between changes in depression-like behaviors and plasma octanoic acid (OA) levels, indicating a potential role for OA in cold-induced depression-like behaviors. OA supplementation effectively alleviated depression-like behaviors and acute cold-induced neuroinflammation. Additionally, OA significantly attenuated lipopolysaccharide-induced depression-like behaviors and neuroinflammation. Mechanistically, OA inhibited microglial activation by targeting the aldo-keto reductase family 1 member B1-prostaglandin F2α pathway, thereby suppressing p65 nuclear translocation and reducing neuroinflammation. This study elucidated a potential OA target in neuroinflammatory response modulation, providing an effective strategy for preventing negative mood and maintaining emotional homeostasis.