AbstractBorna disease virus (BoDV‐1) can infect the hippocampus and limbic lobes of newborn rodents, causing cognitive deficits and abnormal behavior. Studies have found that neuroinflammation caused by viral infection in early life can affect brain development and impair learning and memory function, revealing the important role of neuroinflammation in cognitive impairment caused by viral infection. However, there is no research to explore the pathogenic mechanism of BoDV‐1 in cognition from the direction of neuroinflammation. We established a BoDV‐1 infection model in rats, and tested the learning and memory impairment by Morris water maze (MWM) experiment. RNAseq was introduced to detect changes in the gene expression profile of BoDV‐1 infection, focusing on inflammation factors and related signaling pathways. BoDV‐1 infection impairs the learning and memory of Sprague‐Dawley rats in the MWM test and increases the expression of inflammatory cytokines in the hippocampus. RNAseq analysis found 986 differentially expressed genes (DEGs), of which 845 genes were upregulated and 141 genes were downregulated, and 28 genes were found to be enriched in the toll‐like receptor (TLR) pathway. The expression of TLR4, MyD88, and IRF5 in the hippocampus was significantly changed in the BoDV‐1 group. Our results indicate that BoDV‐1 infection stimulates TLR4/MyD88/IRF5 pathway activation, causing the release of downstream inflammatory factors, which leads to neuroinflammation in rats. Neuroinflammation may play a significant role in learning and memory impairment caused by BoDV‐1 infection.