Early social stress, novelty seeking, and impulsive behavior

描述（由申请人提供）：新奇寻求行为促进发现和构建有关环境的新知识的能力。婴儿期对新奇事物的更大偏好预示着儿童和年轻人在智力、语言、记忆和信息处理速度测试中的得分更高。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、无保护措施的性行为、未成年人饮酒以及其他形式的酒精和药物滥用的流行。最近，我们发现，新奇寻求在动物模型中介导的影响，早期的社会压力对随后的抵抗灭绝的条件位置偏好可卡因。我们的初步证据进一步表明，早期暴露于社会压力诱导腹侧而非背侧纹状体多巴胺D2受体（DRD2）基因表达的长期下调。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可用性减少与新奇寻求和相关的适应不良形式的预期冲动有关，但不是在早期社会压力的背景下。因此，我们计划测试 早期社会应激通过表观遗传机制下调腹侧纹状体中DRD2基因表达的假设（即，增加的DNA甲基化），从而增加预期冲动。具体而言，我们致力于实现以下三个目标。目标1。通过对纹状体脑组织DNA进行亚硫酸氢盐测序，确定早期社会应激是否增加腹侧而非背侧纹状体中DRD2基因启动子甲基化。目标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非背侧纹状体中DRD2的可用性。目标3.确定早期的社会压力是否会增加预期的冲动性，而不会损害非预期形式的冲动行为。旨在解决这些目标的研究将为理解早期社会压力对广泛重要的健康相关行为方面的长期影响的途径提供机制性见解。 公共卫生相关性：了解介导社会压力对健康相关行为影响的机制对公共卫生的影响可能相当大。根据世界卫生组织的数据，到2020年，与压力有关的心理健康障碍将成为所有医疗残疾的第二大原因。美国压力研究所已经确定，目前超过70%的医疗访问与压力有关，每年总共花费国家420亿美元。因此，迫切需要新的机制性见解来指导公共卫生政策和干预措施的制定，以减轻暴露于早期社会压力的有害长期影响。

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. PUBLIC HEALTH RELEVANCE: The public health impacts of understanding the mechanisms that mediate the effects of social stress on health-related behavior are potentially quite high. According to the World Health Organization, stress- related mental health disorders will be the second leading cause of all medical disabilities by the year 2020. The American Institute of Stress has determined that currently more than 70% of all medical visits are stress-related and collectively cost the nation 42 billion dollars each year. Consequently, there is an urgent need for new mechanistic insights to guide the development of public health policies and interventions designed to alleviate the detrimental long-term effects of exposure to early social stress.