Abstract

Fine particulate matter (PM 2.5 ) is a pervasive air pollutant that has been linked to adverse mental health outcomes, but whether subchronic exposure modifies susceptibility to chronic stress-related depression-like pathology remains unclear. In this study, mice were subjected to subchronic PM 2.5 inhalation exposure, chronic unpredictable mild stress (CUMS), or their combination to assess behavioral changes and hippocampal injury. Behavioral tests, histopathology, biochemical assays, transcriptomic profiling, electrophysiological recordings, and analyses of synaptic plasticity-related markers were performed. PM 2.5 exposure alone did not induce overt depression-like or anxiety-like behaviors, although it caused modest neurobiological alterations. In contrast, compared with CUMS alone, combined PM 2.5 and CUMS exposure aggravated anhedonia-related, behavioral despair-related, and anxiety-related abnormalities, particularly at later stages. These behavioral changes were accompanied by more pronounced hippocampal injury, enhanced neuroinflammation, disrupted oxidative stress homeostasis, and impaired synaptic plasticity. These findings suggest that subchronic PM 2.5 exposure may act as an environmental modifier of chronic stress-induced depression-like pathology, and that the aggravated behavioral phenotype is associated with hippocampal neuroinflammation, oxidative stress, and synaptic dysfunction.