Recent studies, including our own, suggest that qualities acquired from one's life experiences while young can be passed on epigenetically to future generations. However, the molecular mechanisms remain poorly understood. This "Lamarkian" type of inheritance implies that one's vulnerability to psychiatric disease may be enhanced if one's parents experienced adverse environments before child-bearing age. This application is based on our new published and unpublished data that support this hypothesis and also adds a new dimension by demonstrating that a parent does not have to display the effects of their environment to transmit them across generations. In particular, we found that exposure to chronic social instability stress during adolescence and early adulthood elevates anxiety and dysfunctional social interactions across three generations of mice. Moreover, chronic exposure of adolescent, but not adult, mice to nicotine induces depressive-like behaviors in future offspring. Remarkably, in both cases only female offspring are affected, yet transmission of these phenotypes can occur through the male lineage even if males are only present during mating. The goal of this 2-year project is to begin to reveal the molecular mechanisms involved in the paternal transmission of these environmentally-induced behavior alterations across generations by testing the hypothesis that changes in DNA methylation and/or altered RNA content can be detected in sperm from "carrier" males. It is anticipated that these findings will drive future studies designed to reveal how these changes in sperm mediate the paternal transmission process, and stimulate investigations into whether this newly appreciated form of inheritance contributes to psychiatric disorders in humans.
The susceptibility to psychiatric disorders varies greatly among individuals. It is thought to be due to both the forms of genes one inherits from one's parents and one's personal experiences. This application will begin to test the hypothesis that another component of susceptibility is inherited from changes in the methylation state of sperm DNA or the composition of sperm RNA that occur in response to the exposure of one's father to social stress in the form of social instability or addictive drugs in the form of nicotine when he was young.