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，表明一个人年轻时从生活经历中获得的品质可以从表观遗传中遗传给后代。然而，其分子机制仍然知之甚少。这种“拉马尔基式”遗传意味着，如果一个人的父母在生育年龄之前经历了不利的环境，那么他对精神疾病的易感性可能会增加。这个应用程序基于我们新发布和未发布的数据，这些数据支持这一假设，并通过证明父母不必展示他们环境的影响来将这些影响传递给几代人，从而增加了一个新的维度。特别是，我们发现，在青春期和成年期早期暴露在慢性社会不稳定压力下，会在三代小鼠中增加焦虑和功能失调的社会互动。此外，长期接触尼古丁的青春期小鼠，而不是成年小鼠，会在未来的后代中诱导类似抑郁的行为。值得注意的是，在这两种情况下，只有雌性后代会受到影响，但这些表型的传播可以通过雄性血统发生，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甲基化变化和/或RNA含量变化可以在男性携带者的精子中检测到这一假设，开始揭示这些环境诱导的行为变化的父系遗传的分子机制。预计这些发现将推动未来的研究，旨在揭示精子的这些变化如何调节父系传播过程，并促使人们调查这种新发现的遗传形式是否会导致人类的精神障碍。

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 This application is based on our new published and unpublished data that support this hypothesis and also adds a new dimension by demonstrating that a parent does not have to display the effects of their environment to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