Long-term Cognitive and Neuroanatomical Consequences of Childhood Stress

描述（由申请人提供）：确定疾病风险的个体差异如何出现是生物医学研究的主要目标。早期生活经历可能是终生患病风险和其他不良后果的关键。确定早期经历在整个生命周期中改变健康轨迹的范围、程度和机制，对公共卫生具有非常高的意义。幼儿期是预防和干预的一个极其宝贵的窗口期，旨在避免人类痛苦和经济负担方面的成本，否则这些成本有可能在个人的一生中不断升级。童年时期的逆境是一生中持续存在的一系列负面健康结果的潜在风险因素。揭示这些早期经历如何增加健康轨迹的风险和变化，对于制定更好的预防、干预和治疗策略以改善人类健康非常重要。动物模型和动物研究对实现这些目标至关重要。非人类灵长类动物的研究为理解早期不良经历对复杂的生物行为、认知和神经生物学功能的影响提供了重要而独特的机会，这些不良经历在相对较长的生命周期中与人类的成熟过程相似。然而，针对猴子早期生活事件的终身影响的纵向研究却异常稀少。缺乏关于早期不良经历如何改变中老年时期的发育和健康的信息，这对使用这种动物模型进行研究提出了挑战。这里提出的研究的广泛目标是解决这些关键的知识差距。这些研究将使用纵向研究方法来确定不同的早期养育经历（托儿所与母亲抚养）对成年恒河猴（14-19岁；大约在40-60岁之间）中年行为和大脑的特定方面的影响。本研究的具体目的是：1)确定早期差别饲养对恒河猴特定行为方面的长期影响；2)利用磁共振成像技术（MRI）确定早期差别抚养对脑形态和脑成分整体和特定方面的长期影响；(3)评估幼儿和母猴在认知、学习和记忆测试中的表现与大脑结构方面的关系；4)评估中年成熟期大脑和行为的年龄相关变化。这些研究将利用一种独特的现有动物种群，在中年成熟期的认知、学习、记忆和大脑方面产生新的、立即有用的数据。总之，拟议的研究将解决关于长期存在的童年逆境动物模型的悬而未决的问题，并将产生关于早期经历对整个生命周期健康影响的新信息。

DESCRIPTION (provided by applicant): Identifying how individual differences in risk for disease emerge is a major target for biomedical research. Early life experiences may be pivotal in lifetime risk of disease and other adverse outcomes. The public health significance of identifying the scope, extent, and mechanisms by which early experiences alter health trajectories across the lifespan is extraordinarily high. Early childhood represents a critically valuable window for prevention and intervention aimed at averting costs, both in terms of human suffering and economic burden, that otherwise have the potential to escalate across an individual's life. Adversity in childhood is a potent risk factor for a range of negative health outcomes persisting throughout the lifespan. Uncovering how these early experiences generate increased risk and variation in health trajectories is important for the development of better prevention, intervention, and treatment strategies to improve human health. Animal models and animal research are essential to achieving these goals. Nonhuman primate studies offer significant and unique opportunities for understanding the consequences of early adverse experiences on complex biobehavioral, cognitive, and neurobiological functions across a relatively long lifespan that parallels humans in terms of maturational processes. Longitudinal research that addresses the lifelong consequences of early life events in monkeys is exceptionally sparse, however. The dearth of information about how early adverse experiences alter development and health across the middle- and later-life periods poses a challenge to use of this animal model for research. The broad goal of the research proposed here is to address these critical gaps in knowledge. The studies will use a longitudinal research approach to identify the consequences of different early rearing experiences (nursery- versus mother-reared) on specific aspects of behavior and brain in middle- age (14-19 years; approximate range within 40-60 human years) in an existing population of adult rhesus monkeys. The specific aims of this research are: 1) To determine the long-term effects of early differential rearing on specific aspects of behavior in rhesus macaques; 2) To determine the long-term effects of early differential rearing on both global and specific aspects of brain morphology and cerebral composition using magnetic resonance imaging (MRI); 3) To assess the relationship between performance on cognitive, learning and memory tests and structural aspects of the brain in these nursery- and mother-reared monkeys; and, 4) To evaluate age-related changes in both brain and behavior across the middle-age maturational period. These studies will leverage a unique existing population of animals to produce new and immediately useful data on cognition, learning, memory, and brain in the middle-age maturational period. Together, the proposed studies will address unanswered questions about a long-standing animal model of childhood adversity and will produce novel information about the consequences of early experience on health across the lifespan. PUBLIC HEALTH RELEVANCE: Childhood impoverishment, stress, and adversity are part of a risk pathway for a broad range of deleterious health outcomes across the lifespan. Understanding how early experiences alter the trajectory of healthy development is critically important to research on human health. The proposed studies will provide important information about the long-term consequences of early stress on brain and cognitive behavior in adult monkeys and, in turn, will shed light on how early experience alters health trajectories across the lifespan and how we might develop better treatment, prevention, and intervention strategies to promote human health.