238. CHRONIC EXPOSURE TO AIR POLLUTANTS LEADS TO COGNITIVE DECLINE MEDIATED BY GUT-DERIVED METABOLITE TMAO IN ADULT MICE

Abstract Background Particulate matter (PM2.5), with an aerodynamic diameter of 2.5μm or less, significantly contributes to air pollution and is mainly generated through the combustion of fossil fuel and coal in residential, industrial, and energy sectors. It impacts the central nervous system (CNS) directly crossing the blood-brain barrier or through the gut-brain axis. Recent studies indicate that PM2.5 disrupts neurogenesis by crossing the blood-brain barrier causing structural and functional changes in the hippocampus. However, the effects of PM2.5 on cognitive function through modulation of gut microbiota and its derived metabolites remains largely unknown. Aims & Objectives This study aimed to investigate the possible mechanism of PM2.5 induced-cognitive deficits mediated by gut-derived metabolite Trimethylamine N-oxide (TMAO) through the gut-brain axis. Method Male and female C57BL/6J mice (5-6 weeks old) received either artificial lung fluid (ALF) as control or 2.5 μg/μl ambient PM2.5 dissolved in ALF via intratracheal instillation every other day for three weeks. A series of behavior tests including open field (OF), novel object recognition (NOR), Y-maze, and forced swimming (FS) were performed. Immunohistochemistry and electrophysiological field recording were also conducted. Results PM2.5 exposure increased immobility in the forced swimming test and reduced time in the center of the open field test, indicating a significant increase in depression- and anxiety-like behaviors. Moreover, a decrease in exploration index to novel object in the novel object recognition test and to novel arm in the Y-maze test suggested significant impairments in short-term and spatial memory after PM2.5 exposure. Chronic exposure to PM2.5 also decreased the number of cell proliferation and neuronal differentiation markers in the hippocampus, suggesting impaired adult neurogenesis. Exposure to PM2.5 also decreased field excitatory postsynaptic potentials (fEPSPs), the input-output curve, and the paired-pulse ratio (PPR) in the dentate gyrus indicating the deficits in learning and memory and synaptic efficacy. During PM2.5 exposure, mice were administered one percent 3,3-dimethyl-1-butanol (DMB), a drug to inhibit TMAO, via drinking water, this treatment ameliorated cognitive deficits by improving depression- and anxiety-like behaviors, short-term and spatial memory, neurogenesis, and synaptic plasticity. Discussion & Conclusions The results suggested that PM2.5 exposure may induce cognitive impairment by inducing a deficit in neurogenesis and synaptic plasticity mediated by TMAO in the hippocampus.