Abstract： Objective:To study the differential protein and signal pathway related to the impairment of learning and memory ability of offspring caused by chronic stress during pregnancy and explore the possible mechanism.Methods:From July to October 2019, sixteen SPF free female SD rats aged 80-90 days, weighing (200±20) g. Twelve SPF grade male SD rats aged 90-100 days, weighing (220±20) g. After a week of adaptive feeding, the female rats were randomly divided into control group and model group (8 rats in each group) , male rats were divided into control mating group ( n=8) and model mating group ( n=4) . Chronic unpredictable mild stress (CUMS) model was established and stimulated continuously for 21 days. One day before stress, the first, seventh, fourteenth and 21th day after stress, the blood was collected from the inner canthus vein of the female rats, and the content of corticosterone was determined. Morris water maze test was used to detect the spatial learning and memory ability of offspring rats. The morphological changes of hippocampus were observed by HE and Nissl staining. The proteomic correlation analysis of offspring rats' hippocampus was performed by isobaric tags for relative and absolute quantification (iTRAQ) technique. Results:Compared with the control group, the content of plasma corticosterone in the model group was significantly higher ( F=7.717, P<0.05) , and the model was successfully established. In Morris water maze test, compared with the control offspring group, the escape latency was longer, the average swimming speed was lower, the number of crossing platform was less, and the target quadrant run was shorter in the model offspring group ( P<0.05) . The pathological results showed that the morphology of cells in the hippocampal tissue of the model offspring group was irregular, the number of neurons was small, Nissl body was unevenly distributed, the volume was small and the number was small. Mass spectrometry analysis showed that a total of 5065 proteins were screened out in the two offspring groups, and 26 proteins were differentially expressed ( P<0.05) , of which 19 proteins were up-regulated and 7 proteins were down regulated. The differential proteins were mainly involved in 23 biological processes, 14 cellular components and 9 molecular functions. Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis showed that 57 pathways were enriched, of which 8 signaling pathways were significantly enriched ( P<0.05) . There were 5 signaling pathways that might be involved in the impairment of learning and memory ability of offspring, including neuroactive ligand receptor interaction, cGMP-PKG signaling pathway, adhesion and connection, adhesion and connection FoxO signaling pathway and Notch signaling pathway, mainly including tyrosine protein kinase receptor, tyrosine kinase receptor and Notch signaling pathway, and α2A adrenergic receptor, cGMP dependent protein kinase and other differential proteins may be involved in the injury process. Conclusion:The damage of learning and memory ability of offspring may be caused by chronic stress during pregnancy rats. The enriched signal pathway and key differential proteins of proteomics may play an important role in the process of damage.