Early social stress, novelty seeking, and impulsive behavior

描述(由申请人提供)：寻求新奇的行为促进了发现和构建关于环境的新知识的能力。婴儿期对新奇事物的偏好越高，儿童和年轻人在智力、语言、记忆和信息处理速度方面的测试分数就会越高。然而，追求新奇可能代价高昂，因为它增加了鲁莽驾驶、病态赌博、无保护的性行为、未成年饮酒和其他形式的酒精和药物滥用的流行。最近，我们在一个动物模型中发现，在早期社会压力对随后抵抗对可卡因的条件地偏好的消亡的抵抗中，动物模型中的新鲜感起中介作用。我们的初步证据进一步表明，早期暴露于社会应激导致腹侧纹状体多巴胺D2受体(DRD2)基因表达的长期下调，而不是背侧纹状体。在人类和动物模型中，通过正电子发射断层扫描(PET)确定的腹侧纹状体DRD2可用性降低与新奇寻求和相关的预期冲动的适应不良形式有关，但与早期社会应激无关。因此，我们计划测试 早期社会压力通过表观遗传机制(即DNA甲基化增加)下调腹侧纹状体DRD2基因表达从而增加预期冲动的假说。具体地说，我们解决了以下三个目标。目的1.通过纹状体脑组织DNA亚硫酸氢盐测序，确定早期社会应激是否增加腹侧纹状体DRD2基因启动子甲基化，而不是背侧纹状体DRD2基因启动子甲基化。目的2.通过正电子发射断层扫描确定早期社会应激是否会降低腹侧而不是背侧纹状体中DRD2的利用率。目的3.确定早期社会压力是否在不损害非预期形式的冲动行为的情况下增加预期冲动。旨在解决这些目标的研究将为理解早期社会压力对与健康相关的行为的广泛重要方面的长期影响的途径提供机械性的见解。

DESCRIPTION (provided by applicant): Novelty seeking behavior promotes the ability to discover and construct new knowledge about the environment. Greater preferences for novelty during infancy predict higher scores on tests of intelligence, language, memory, and speed of information processing in children and young adults. Novelty seeking can be costly, however, as it increases the prevalence of reckless driving, pathological gambling, unprotected sex, under-age drinking, and other forms of alcohol and drug abuse. Recently, we discovered that novelty seeking in an animal model mediates the effects of early social stress on subsequent resistance to extinction of a conditioned place preference for cocaine. Our preliminary evidence further suggests that early exposure to social stress induces long-lasting downregulation of dopamine D2 receptor (DRD2) gene expression in ventral but not dorsal striatum. Diminished ventral striatal DRD2 availability determined in vivo by positron emission tomography (PET) has been linked in humans and animal models to novelty seeking and related maladaptive forms of anticipatory impulsivity, but not in the context of early social stress. Therefore, we plan to test the hypothesis that early social stress downregulates DRD2 gene expression in ventral striatum via epigenetic mechanisms (i.e., increased DNA methylation) and thereby increases anticipatory impulsivity. Specifically, we address the following three aims. Aim 1. Determine whether early social stress increases DRD2 gene promoter methylation in ventral but not dorsal striatum assessed by bisulfite sequencing of DNA from striatal brain tissues. Aim 2. Determine whether early social stress decreases DRD2 availability in ventral but not dorsal striatum assessed in vivo by positron emission tomography. Aim 3. Determine whether early social stress increases anticipatory impulsivity without impairing non-anticipatory forms of impulsive behavior. The studies designed to address these aims will provide mechanistic insights for understanding the pathways that mediate the long-term effects of early social stress on broadly important health-related aspects of behavior.