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Deployment-related exposures to organophosphate (OP) compounds are implicated for Gulf War Illness (GWI) development in First GW veterans. However, reasons for the persistence of GWI are not fully understood. Epigenetic modifications to chromatin are regulatory mechanisms that can adaptively or maladaptively respond to external stimuli. These include DNA methylation and histone acetylation. DNA methylation changes have been reported in GWI but the role of histone acetylation in GWI has been less explored, despite its importance as an epigenetic mechanism for neurological disorders. Male Sprague-Dawley rats were exposed to OP diisopropyl fluorophosphate (DFP, 0.5 mg/kg s.c., 5-d) and 6-m later brains were dissected for hippocampus. Western blotting, activity assays and chromatin immunoprecipitation (ChIP) were utilized for epigenetic analyses. Behavior was assessed using the Forced Swim Test (FST) and the Elevated Plus Maze (EPM). We observed a significant upregulation in HDAC1 protein along with a significant increase in HDAC enzyme activity in the hippocampus of DFP rats. A locus-specific ChIP study revealed decreases in H3K9ac at the brain derived neurotrophic factor (Bdnf) promoter IV coupled with a significant decrease in BDNF protein in DFP rat hippocampus. Treatment with HDAC inhibitor valproic acid reduced HDAC activity and decreased the FST immobility time in DFP rats. Our research suggests that epigenetic alterations to histone acetylation pathways and decreased BDNF expression could represent novel mechanisms for GWI symptomatology and may provide new targets for developing effective drugs for GWI treatment. • Repeated, low-dose DFP exposure in rats elicited chronic depression-like state • Increased in hippocampal HDAC activity and HDAC1 protein were noted in DFP rats • Decreased acetylated histone H3K9 at bdnf promoter IV site along with reduced BDNF protein were noted in DFP rats • Valproic acid blocked HDAC activity and was associated with antidepressant-like effect in DFP rats [ABSTRACT FROM AUTHOR]