Optimal hydration is essential to implement normal physiological processes and maintain healthy life, therefore, dehydration deteriorates a range of biological functions in various tissues. A number of evidences suggest that dehydration negatively affect cognitive functions in brain, however, the underlying molecular mechanisms were not elucidated yet. In this study, we investigate the transcriptional networks of hippocampus in dehydrated mice. Dehydration was induced by the time-limit access to a water bottle (15 mins per day) in 3 week old C57BL/6 male mice. First, we examined the spatial learning ability of dehydrated mice using Barnes maze test. The latency to find a target hole was four times longer in dehydrated mice compared to control mice that accessed a water bottle freely. Transcriptiome in hippocampus of dehydrated mice were sequenced using Next Generation Sequencing and compared with those of control mice. Bioinformatic analysis presented the transcriptional networks of CREB and LTB signalling were significantly dysregulated by dehydration. In addition, a series of neurotrophic factors were examined for their expressions, the transcript level BDNF was significantly lower in dehydrated mice, only in hippocampus not in other regions of brain. These results suggest new insights into the mechanism by which dehydration deteriorates normal development of cognitive functions