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。婴儿时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获得更高的分数。然而，追求新奇的代价是昂贵的，因为它增加了鲁莽驾驶、病态赌博、无保护的性行为、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，我们在一个动物模型中发现，新奇寻求介导了早期社会压力对可卡因条件位置偏好灭绝的后续抵抗的影响。我们的初步证据进一步表明，早期暴露于社会压力会导致腹侧纹状体而非背侧纹状体多巴胺D2受体（DRD2）基因表达的长期下调。在人体和动物模型中，通过正电子发射断层扫描（PET）测定的腹侧纹状体DRD2可用性减少与寻求新奇和相关的预期冲动性的不适应形式有关，但在早期社会压力的背景下没有联系。因此，我们计划进行测试

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.