Environment and Gene Effects on Brain and Behavior

描述（由申请人提供）：发育期铅暴露可能影响认知发育和晚年认知功能的一种重要方式是通过表观遗传修饰，特别是通过调节DNA甲基化。最近的研究表明，成年人大脑中的DNA甲基化是高度动态的，并且前额叶皮层（PFC）和海马中甲基化的动态调节在记忆的形成、巩固和维持中起着不可或缺的作用。初步数据表明，PFC和海马中的DNA甲基化受到发育铅暴露在静息条件下和在学习和记忆过程中，干扰在学习和记忆过程中所需的甲基化和基因转录的正常动态调节，导致认知缺陷。这些影响的铅似乎是不同的男性和女性中表达，铅暴露的发育时间的影响，并可能通过应变特定的表观遗传影响的个人遗传组成进行修改。我们的长期目标是了解发育期铅暴露如何对大脑和行为产生长期影响。这里的目标，这是我们追求这些目标的下一步，是更好地了解铅对大脑的表观遗传效应以及这些效应如何影响行为。我们的目标是确定低水平铅暴露如何影响学习和记忆过程中PFC和海马中特定基因的动态甲基化，以及这些影响在多大程度上导致男性和女性以及不同品系大鼠的认知缺陷。我们的中心假设是，铅暴露将改变PFC和海马中关键学习/记忆相关基因的DNA甲基化的动态调节，并且铅的这种表观遗传影响将因性别和品系而异。这项研究的目标将通过追求以下目标来实现：1）确定低水平铅暴露对学习和记忆过程中DNA甲基化动态调节的影响，并研究这些影响如何影响我们鉴定为对铅影响高度敏感的品系中的男性和女性的行为和认知相关基因表达（Long Evans）和相对抗性的菌株（Sprague道利）。我们的假设是，将有异常的动态DNA甲基化，导致学习/记忆相关基因的异常调节与相关的认知缺陷，这些影响将被性别和应变修改; 2）确定DNA甲基化的药理学调节影响铅暴露动物的认知结果和调节学习/记忆相关基因表达的程度。我们推测，异常的DNA甲基化可以被人为操纵，可能会重新设置铅诱导的变化，并积极影响认知结果。拟议中的研究从目前的赠款延伸，并将确定铅暴露可能影响行为的表观遗传机制。结果预计将有重要的积极影响，因为低水平铅暴露的广泛危险，并确定潜在的干预措施，可能会改善被认为是永久性的负面结果的可能性。

DESCRIPTION (provided by applicant): An important way in which developmental Pb exposure may influence cognitive development and later life cognitive functioning is through epigenetic modifications and specifically, through modulating DNA methylation. Recent studies show that DNA methylation in the adult brain is highly dynamic and that the dynamic regulation of methylation in the prefrontal cortex (PFC) and hippocampus together play integral roles in memory formation, consolidation, and maintenance. Preliminary data show that DNA methylation in PFC and hippocampus are affected by developmental Pb exposure under resting conditions and during learning and memory, interfering with normal dynamic regulation of methylation and gene transcription necessary during learning and memory, leading to cognitive deficits. These effects of Pb appear to be expressed differently in males and females, are influenced by developmental timing of Pb exposure, and may be modified by individual genetic makeup through strain-specific epigenetic influences. Our long-term goal is to understand how developmental Pb exposure exerts long-term effects on the brain and behavior. The objective here, which is our next step in pursuit of these goals, is to better understand epigenetic effects of Pb on the brain and how these effects influence behavior. Our goal is to determine how low level Pb exposure affects dynamic methylation of specific genes in PFC and hippocampus during learning and memory and the extent to which these effects contribute to cognitive deficits in males and females and in different strains of rats. Our central hypothesis, is that Pb exposure will alter the dynamic regulation of DNA methylation of key learning/memory related genes in the PFC and hippocampus and that this epigenetic influence of Pb will vary by sex and strain. The objectives of this research will be accomplished by pursuing the following aims: 1) Determine effects of low level Pb exposure on the dynamic modulation of DNA methylation during learning and memory and examine how these effects influence behavior and cognition-related gene expression in males and females in a strain identified by us to be highly susceptible to the effects of Pb (Long Evans) and a strain relatively resistant (Sprague Dawley). Our hypothesis is that there will be aberrant dynamic DNA methylation resulting in abnormal modulation of learning/memory-related genes with associated cognitive deficits and these effects will be modified by sex and strain; 2) Determine the extent to which pharmacological modulation of DNA methylation influences cognitive outcomes in Pb-exposed animals and modulates learning/memory-related gene expression. We postulate that aberrant DNA methylation can be pharmacologically manipulated, potentially re-setting Pb-induced changes and positively influencing cognitive outcome. The proposed studies extend from the current grant and will identify epigenetic mechanisms through which Pb exposure may influence behavior. Results are expected to have important positive impact because of the widespread danger from low level Pb exposure and the possibility of identifying potential interventions that may improve negative outcomes assumed to be permanent.