Docosahexaenoic acid attenuates anxiety-like behaviors and restores astrocytic function and serotonergic integrity following acute manganese exposure in mice

Abstract

Manganese (Mn) overexposure induces neurotoxicity characterized by motor and cognitive impairments, as well as anxiety-like behaviors. The current study aimed to investigate the neuroprotective effects of docosahexaenoic acid (DHA) against acute Mn-induced neurobehavioral and neuropathological alterations in adult Swiss mice. Animals were assigned to four groups: control, Mn-intoxicated, Mn + DHA-treated, and DHA-treated. Anxiety-like behaviors were assessed using the open field, elevated plus maze, and marble burying tests, alongside immunohistochemical analyses of astrocytes and serotonergic neurons. Mn-intoxicated mice exhibited heightened anxiety-like behaviors, reduced serotonergic neuronal labeling in the dorsal raphe nucleus (DRN), and increased astrocytic reactivity in the hippocampus, indicated by elevated glial fibrillary acidic protein (GFAP) immunoreactivity. DHA pretreatment significantly attenuated these behavioral deficits and neuropathological changes, suggesting protective effects against Mn-induced altered serotoninergic neurotransmission and astrocytic activation. Overall, acute Mn exposure was associated with anxiety-like behaviors, disrupted serotoninergic neurotransmission, and astrocytic morphological alterations, whereas DHA exerted robust neuroprotective effects. These findings highlight DHA as a potential therapeutic candidate for Mn-induced neurotoxicity.