EMORY CONTE CENTER FOR THE NEUROSCIENCE OF MENTAL DISORDERS: PRIMATE CORE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。埃默里孔特精神疾病神经科学中心-灵长类核心。本工作的主要目标是在恒河猴中建立和表征非人类灵长类动物的表观遗传早期生活压力模型。早期压力经历与成年后的焦虑和情感障碍风险相关的潜在灵长类动物模型已经被提出了许多程序。从长期的婴儿隔离范例到短期（1-24小时）的母婴分离，然后再团聚。前者会对社交能力和对压力的敏感性造成近乎永久性的破坏。后者在社会行为上产生剧烈的变化，在对压力的敏感性上产生短暂的变化，但显然没有长期的行为缺陷。我们在恒河猴发育的关键时期（3-6个月大）实施了一项重复母子分离的计划。这个项目的目的是为埃默里精神疾病神经科学中心提供猴子早期发育压力。我们研究了母亲反复分离对动物情绪行为和下丘脑轴功能的短期和长期影响。反复的母亲分离使婴儿过敏？HPA轴对应激反应，特别是在具有5-羟色胺转运基因启动子区域短等位基因（rh5-HTTLPR）的女性和婴儿中。作为青少年，母亲分离的受试者表现出增强的惊吓反应性，扁平的皮质醇昼夜节律和垂体-肾上腺功能的改变，通过CRF和ACTH药理学挑战检测。大多数这些改变表明，早期不良经历导致CRF系统和HPA轴的过度活跃，随后在不同水平的轴上出现代偿性下调。阴性结果受性别和血清素转运体基因变异的强烈影响。虽然这些因素之间的相互作用是复杂的，但女性和具有短等位基因的受试者更容易受到母亲分离的影响。我们对这些动物进行纵向跟踪，包括目前的生长、代谢和免疫功能的研究，以及使用正电子发射断层扫描（PET）神经成像的大脑血清素能功能的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Emory Conte Center for the Neuroscience of Mental Disorders - Primate Core. The major goal of this work is to produce and characterize a non-human primate epigenetic early life stress model in rhesus monkeys. A number of procedures have been offered as potential primate models of early stress experience associated with subsequent risk for anxiety and affective disorders in adulthood. These range from the chronic infant isolation paradigms to short-term (1-24 hr) mother-infant separations followed by reunion. The former produce near-permanent disruptions in social competence and sensitivity to stress. The latter produce acute changes in social behavior and transient changes in sensitivity to stress, but apparently no long-term behavioral deficits. We have imposed a schedule of repeated mother-infant separations in rhesus macaques during a critical period of development (3-6 months of age). The purpose of this project is to provide monkeys with an early developmental stress to the Emory Center for the Neuroscience of Mental Disorders. We have investigated the short-term and long-term effects of repeated maternal separation on emotional behavior and HPA axis function of the animals. Repeated maternal separation sensitized the infants? HPA axis responses to stress, particularly in females and infants with the short allele of the promoter region of the serotonin transporter gene (rh5-HTTLPR). As juveniles, maternally-separated subjects exhibited enhanced startle reactivity, flattened cortisol diurnal rhythms and alterations in pituitary-adrenal function detected with CRF and ACTH pharmacological challenges. Most of these alterations suggest that the early adverse experience caused hyperactivity of CRF systems and HPA axis, followed by a subsequent compensatory downregulation at different levels of the axis. The negative outcomes were strongly affected by sex and serotonin transporter gene variation. Although the interactions between these factors are complex, females and subjects with the short allele were more vulnerable to the effects of maternal separations. We are following the animals longitudinally, including current studies of growth, metabolism and immune function, as well as of brain serotonergic function using positron emission tomography (PET) neuroimaging.