Sex, drugs, and transgenerational inheritance: Are the kids alright?

The occurrence of neuropsychiatric disorders and substance abuse is subject to familial inheritance (nature) as well influence from the environment (nurture). In addition, familial patterns of behavior and disease are also mediated by transgenerational epigenetic inheritance. The dynamic nature of the epigenome allows for exposures to stress, drugs of abuse, environmental toxins, and even changes in diet to produce changes in gene expression. In addition these changes can be inherited by offspring. Therefore, offspring behavior and quality of life are shaped by their own experiences as well as the experiences of their parents and more distant relatives. The studies in this dissertation had two objectives: first to identify the transgenerational inheritance of adolescent stress exposure and its effects on offspring behavior including response to nicotine and second, to determine the cross-generational interaction of nicotine and stress exposures on offspring behavior. To address the first objective, we exposed male and female mice to adolescent stress exposure, determined the long-term effects of exposure on their behavior, and identified changes in phenotype in their F1 and F2 offspring. We found that adolescent stress exposure produced changes in anxiety, startle response, and gene expression in adulthood that was not found when the same stress exposure occurred in adult mice. In addition, we found that transgenerational inheritance of adolescent stress exposure promoted sex- and lineage-dependent changes in anxiety, depression, startle, and response to nicotine in F1 and F2 offspring. Furthermore, to determine if parental stress exposure influenced gene expression in the brains of offspring we analyzed the transcriptome of F1 males and found 240 differentially expressed genes in the amygdala of males whose fathers were exposed to stress. In our final study, we developed a novel multigenerational exposure paradigm and determined that F0 nicotine and F1 stress exposure interact across generations to produce unique phenotypes in F2 and F3 offspring. Together, research from this dissertation provides evidence of an adolescent chronic stress exposure that mediates anxiety in adulthood and is inherited in future generations by reprogramming the brain of offspring, and provides the first example of cross-generational interactions of two environmental exposures to influence offspring phenotype