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Aims: We investigated the protective effects of chemical stimulation of cerebellar fastigial nucleus (FN) on stress gastric mucosal injury (SGMI) and its possible neuro-regulatory mechanisms in rats., Main Methods: Chemical stimulation, electrical stimulation, chemical ablation, electrolytic lesion, and microinjection were used to investigate the effects of FN simulation on SGMI. The model of SGMI was established by restraint and water (21±1°C)-immersion (RWI) for 3h in rats. The gastric mucosal injury index indicated the severity of gastric mucosal injuries., Key Findings: We showed that microinjection of L-glutamic acid into the FN or electrical stimulation of the FN markedly attenuated SGMI. Either chemical lesion of the FN or electrical ablation of the decussation of superior cerebellar peduncle (DSCP) obviously aggravated SGMI. The protective effect of FN stimulation on SGMI was reversed after chemical ablation of the lateral hypothalamic area (LHA). The protective effect of FN was prevented by pretreatment with the glutamic acid decarboxylase antagonist, 3-MPA into the FN or GABA(A) receptor antagonist, bicuculline into the LHA. The protective effect of FN was abolished by pretreatment with sympathectomy. The discharge frequency of greater splanchnic nerve (GSN) was decreased and gastric mucosal blood flow (GMBF) was increased after chemical stimulation of FN. These results indicate that the FN participates in regulation of SGMI, and is a specific area in the CNS for exerting protective effects on the SGMI. The DSCP, LHA and peripheral sympathetic nerve may be involved in this process., Significance: Our findings might provide a new and improved understanding of the cerebellar function and an effective treatment strategy for stress gastric mucosal injury., (Copyright © 2011 Elsevier Inc. All rights reserved.)