Environment and Gene Effects on Brain and Behavior

描述（由申请人提供）：发育性铅暴露可能影响认知发育和晚年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，DNA甲基化在成人大脑中是高度动态的，并且在前额叶皮质（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。初步数据显示，在静息条件下和学习记忆过程中，发育性铅暴露会影响PFC和海马区DNA甲基化，干扰学习记忆过程中甲基化和基因转录的正常动态调节，导致认知缺陷。铅的这些影响似乎在男性和女性中表达不同，受铅暴露的发育时间的影响，并可能通过菌株特异性表观遗传影响被个体基因组成所改变。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，也是我们追求这些目标的下一步，是更好地理解铅对大脑的表观遗传影响，以及这些影响如何影响行为。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雄性和雌性以及不同品系的大鼠的认知缺陷。我们的中心假设是，铅暴露会改变PFC和海马中关键学习/记忆相关基因DNA甲基化的动态调节，并且铅的这种表观遗传影响会因性别和品系而异。本研究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甲基化动态调节的影响，并研究这些影响如何影响我们确定的高易感品系（Long Evans）和相对抗性品系（Sprague Dawley）的雄性和雌性行为和认知相关基因表达。我们的假设是，会有异常的动态DNA甲基化导致异常调节的学习/记忆相关基因与相关的认知缺陷，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在多大程度上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。我们假设异常的DNA甲基化可以被药理学操纵，可能重新设置铅诱导的变化并积极影响认知结果。拟议的研究将从目前的拨款中扩展，并将确定铅暴露可能影响行为的表观遗传机制。由于低水平铅暴露具有广泛的危险，并且有可能确定可能改善被认为是永久性的负面结果的潜在干预措施，因此预计研究结果将产生重要的积极影响。

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.