Paternal Transmission of Environmentally-Induced Behavioral Defects

描述（由申请人提供）：最近的研究，包括我们自己的研究，表明从年轻时的生活经历中获得的品质可以通过表观遗传传递给后代。然而，分子机制仍然知之甚少。这种“拉马克式”遗传意味着，如果父母在生育年龄之前经历了不利的环境，那么一个人对精神疾病的易感性可能会增强。这个应用程序是基于我们新发表的和未发表的数据，这些数据支持这一假设，并通过证明父母不必展示他们的环境的影响来传递他们的后代，从而增加了一个新的维度。特别是，我们发现，在青春期和成年早期暴露于慢性社会不稳定压力会增加三代小鼠的焦虑和功能失调的社会互动。此外，青少年而非成年小鼠长期暴露于尼古丁会导致后代出现类似抑郁的行为。值得注意的是，在这两种情况下，只有雌性后代受到影响，然而这些表型的传播可以通过雄性谱系发生，即使雄性只在交配期间出现。这个为期两年的项目的目标是通过测试DNA甲基化和/或RNA含量改变可以在“携带者”雄性精子中检测到的假设，开始揭示涉及这些环境诱导的行为改变的父系遗传的分子机制。预计这些发现将推动未来的研究，旨在揭示精子中的这些变化如何介导父系遗传过程，并激发对这种新发现的遗传形式是否有助于人类精神疾病的调查。

DESCRIPTION (provided by applicant): 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 This application is based on our new published and unpublished data that support this hypothesis and also adds a new dimension by demonstrating that a parent does not have to display the effects of their environment to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.