The BXDs are a genetically highly divergent set of inbred strains that show significant variation in alcohol preference and stress sensitivity.21, 22 They have been extensively phenotyped for behavioral traits and are particularly suitable for systems genetics analysis of sequence variants, expression differences and linkage to behavioral traits. In this study, we identify an insertion/deletion (indel) mutation in a promoter motif located in the 5′ UTR of Per3 that may underlie this variation in transcript abundance. We also examine the functional consequence of this sequence variant on downstream gene expression in the brain and behavioral traits related to stress and alcohol. As the hippocampus is a site vulnerable to both stress and alcohol,23, 24, 25 we also examined the effects of stress and alcohol on Per3 expression in the hippocampus of the BXDs. We provide evidence that expression of Per3 is both causally associated with behavioral differences in stress response and is influenced by stress and ethanol treatment.
