Vitamin B1 (thiamine) deficiency (TD) has been known to induce cognitive dysfunction including deficits in memory formation known as Wernicke-Korsakoff's syndrome in humans. However, mechanisms by which TD leads to deficits in learning and memory still remain unclear. In this study, to understand them, we examined the effects of pyrithiamine-induced thiamine deficiency (PTD) on learning and memory in mice. PTD-treated mice showed chronic impairments in the formation of hippocampus-dependent memories. Importantly, anatomical analyses indicated that PTD-treated mice displayed significant decreases in sizes of hippocampus and spine density of hippocampal neurons, suggesting the degeneration of hippocampal neurons by PTD-treatment. We next performed RNA-seq analyses of the hippocampus using next-generation sequencing and found that PTD mice showed increases in expressions of inflammation-related genes in the hippocampus and significant decreases in mRNA expressions of transcription factor CREB in the hippocampus, suggesting that PTD showed impaired CREB signaling pathways in the hippocampus. We finally examined the effects of PTD on transgenic mice increasing the CREB activity by expressing a constitutively active CREB mutant in the forebrain (DIEDML mice, Suzuki et al 2011) and found that activation of CREB rescued impairments in hippocampal degeneration and hippocampus-dependent memory by PTD. Taken together, our findings suggest that PTD causes strong inflammation, thereby leading to hippocampal degeneration and subsequent impairments in CREB signaling pathways that play essential roles in memory formation.