Environment and Gene Effects on Brain and Behavior

描述(由申请人提供)：发育铅暴露可能影响认知发展和以后生活认知功能的一个重要途径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，成人大脑中的DNA甲基化是高度动态的，前额叶皮质(PFC)和海马区的甲基化动态调节共同在记忆的形成、巩固和维持中发挥着不可或缺的作用。初步数据显示，在安静状态和学习记忆过程中，发育铅暴露会影响大鼠前脑皮质和海马区DNA甲基化，干扰学习记忆过程中正常甲基化和基因转录的动态调节，导致认知功能障碍。铅的这些效应在男性和女性中的表达似乎不同，受到铅暴露的发育时机的影响，并可能通过品系特有的表观遗传影响而被个体遗传构成所改变。我们的长期目标是了解发育中的铅暴露如何对大脑和行为产生长期影响。这里的目标，也是我们追求这些目标的下一步，是为了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的铅暴露如何影响学习和记忆过程中PFC和海马区特定基因的动态甲基化，以及这些影响在多大程度上导致雄性和雌性以及不同品系的大鼠的认知障碍。我们的中心假设是，铅暴露将改变PFC和海马区关键学习/记忆相关基因DNA甲基化的动态调节，这种表观遗传影响将因性别和品系而异。本研究的目标将通过以下目标来实现：1)确定低水平铅暴露对学习和记忆过程中DNA甲基化的动态调节的影响，并在我们发现对铅(Long Evans)和相对抗性(Spraogue Dawley)的品系高度敏感的品系中，研究这些效应如何影响雄性和雌性的行为和认知相关基因的表达。我们的假设是，存在异常的动态DNA甲基化，导致与认知缺陷相关的学习/记忆相关基因的异常调节，这些影响将因性别和压力而改变；2)决定DNA甲基化的药物调节对铅暴露动物认知结果的影响程度，以及调节学习/记忆相关基因表达的程度。我们推测，异常的DNA甲基化可以被药物操纵，潜在地重新设定铅诱导的变化并对认知结果产生积极影响。拟议中的研究是在目前拨款的基础上进行的，将确定铅暴露可能影响行为的表观遗传机制。预计结果将产生重要的积极影响，因为低水平铅暴露存在广泛的危险，而且有可能确定可能改善假定为永久性的负面结果的潜在干预措施。

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.