Neural Mechanisms of Cognitive Decline Induced by Ricin‐Mediated Cognitive Impairment

Ricin, a highly potent toxin derived from Ricinus communis, poses significant biosecurity concerns due to its potential use as a biological weapon. Although the peripheral toxic effects of ricin have been extensively documented, its impact on the central nervous system, particularly the hippocampus, remains poorly understood. In this study, we systematically investigated the acute neurotoxic effects of systemic ricin exposure on hippocampal structure and function in mice using a multilevel experimental approach. Following dose-response optimization, mice received intraperitoneal injection of ricin (5 μg/kg) and were evaluated at Day 4 (acute phase) and Day 14 (recovery phase). Resting-state functional magnetic resonance imaging revealed significant disruption of whole-brain functional connectivity, with the hippocampal network being most prominently affected. Histological analyses using Nissl and HE staining demonstrated selective neuronal damage in the dentate gyrus and CA3 subregions without widespread cell death. Behavioral assessments confirmed acute impairment of hippocampus-dependent spatial working memory and object recognition memory, with partial recovery by Day 14. Mechanistically, c-FOS immunostaining revealed aberrant neuronal hyperactivation predominantly in CA3, whereas GFAP and IBA1 analyses indicated significant astrocyte reactivity and microglial activation in vulnerable hippocampal subregions. Importantly, both functional connectivity and cognitive performance showed substantial spontaneous recovery within 2 weeks, suggesting reversible rather than permanent damage. These findings provide comprehensive evidence that acute ricin exposure induces transient hippocampal dysfunction through region-specific neuronal stress and neuroinflammatory responses, offering new insights into ricin neurotoxicity and potential therapeutic windows for intervention.