Discovery of quantitative trait loci that mediate the effects of prenatal stress on cocaine and sensorimotor behaviors: Implications for gene by environment interactions that contribute to psychiatric disorders

Gene by environment interactions may be important etiological factors that confer risk of numerous psychiatric disorders. Psychiatric disorders are found to be heritable, indicating genetic variants contribute to risk and resilience. In addition to genetics, early life stress confers significant risk. Prenatal stress (PNS) is associated with numerous disorders and alterations to affect and cognition that suggest profound and enduring consequences. Preclinical studies causally indicate the deleterious effects of PNS on models of psychiatric disorders, including effects on prepulse inhibition (PPI) and cocaine reward and locomotion. The intersection of genetics and PNS has been explored and PNS was found to interact with genetic background. PNS differentially alters PPI and cocaine reward and locomotion in the C57/6J (B6) and DBA/2J (D2) inbred mouse strains. These strains may serve as progenitors for populations that can be utilized in forward genetic studies for discovery of quantitative trait loci (QTLs) that will facilitate discovery of PNS interacting variants. The following will present studies that utilized the BXD recombinant inbred mouse panel, derived from the B6 and D2 strains, to discover QTLs that interact with PNS to alter sensorimotor and cocaine-induced behaviors. A QTL by PNS interaction was discovered for PPI and acute cocaine locomotion. The BXD panel is a genetic reference population that allows for extensive accumulation and sharing of data across studies. Following discovery of these QTLs, publicly available BXD mRNA expression data was utilized to prioritize positional candidate genes. These efforts prioritized several positional candidate genes. In addition to offspring phenotypes, the maternal stress corticosterone response and effects of stress on dam-pup contact were assessed, as heritable maternal stress responses may contribute to strain differences in offspring phenotype, with implications for the interpretation of QTLs. Strain differences in the maternal corticosterone response and the maternal behavior response to stress associated with strain differences in PNS effects on male offspring cocaine phenotypes, suggesting a potential role for genetic variants that moderate the maternal stress response. The results obtained are a preliminary step in identifying genes that interact with PNS to confer risk of psychiatric disease