Abstract In order to explore the differentially expressed genes (DEGs) related to the high incidence of sham-chewing behavior in pregnant sows, 50 sows (Large White × Landrace) were used to observe sham-chewing behavior in early, middle and late gestation. And then according to the number of sham-chewing observed, sows were divided into high incidence of sham-chewing (group H) and low incidence of sham-chewing (group L). After weaning, 4 sows were randomly selected from group H and group L, samples of brain were collected after slaughter, and hypothalamus was sequenced with transcriptome. After bioinformatics analysis, the DEGs were analyzed and enriched in GO and KEGG, afterwards the candidate genes were screened. qRT-PCR was used to verify the accuracy of the sequencing data. Hypothalamic transcriptome results showed that compared with group L, 1286 genes were significantly differentially expressed in group H, among which 934 genes were up-regulated and 352 genes were down-regulated. The results of GO enrichment analysis showed that in biological process, cell component and molecular function, the most significant terms of enrichment are trans-synaptic signaling, neuron part and gated channel activity. These terms are strongly related to synaptic plasticity, synaptic transmission, neurodevelopment and neuropsychiatric diseases, FGF12, SNAP25, CAMK1D, SYNDIG1, GABRD, RBFOX1, CRH, HCN1, HCN4, GLRA3, GRIN2A, ANXA2, MBP and NTF4 genes with high fold change and more in-depth functional research were selected for sham-chewing and depressive emotion-related genes. KEGG enrichment analysis results indicated that differential expressed genes were significantly enriched in 29 pathways, such as neuroactive ligand-receptor interaction, cAMP and Ras-MAPK signaling pathway. In conclusion, the results of hypothalamic transcriptome indicate that there is a molecular genetic basis for depression-like symptoms in group H, the 14 DEGs screened above might be candidate genes involved in high incidence of sham-chewing and depression-like emotion.