Effects of stress and obesity on neurobehavioral development of rhesus macaques

压力和肥胖对恒河猴神经行为发育的影响

• 批准号: 8910120
• 负责人: Jodi Godfrey
• 金额: $ 4.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-13 至 2018-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910120
• 关键词: Adolescent; Adult; Adverse effects; Affect; Amygdaloid structure; Animal Model; Animals; Anxiety; Anxiety Disorders; Atrophic; Behavior; Behavior Control; Behavioral; Biological; Birth; Brain; Child; Childhood; Chronic; Chronic stress; Cocaine; Cognitive; Consumption; Corpus striatum structure; Data; Development; Diet; Diffusion Magnetic Resonance Imaging; Dopamine; Eating; Emotional; Emotional Stress; Emotions; Exhibits; Exposure to; Fatty acid glycerol esters; Female; Fostering; Fright; Functional Magnetic Resonance Imaging; Goals; Health; Hormones; Housing; Hydrocortisone; Impairment; Impulsivity; Infant; Ingestion; Lead; Link; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Monkeys; Mood Disorders; Neurobiology; Neurosciences; Nucleus Accumbens; Obesity; Phenotype; Physiology; Play; Prefrontal Cortex; Pregnancy; Problem behavior; Process; Prospective Studies; Psychopathology; Puberty; Regulation; Research; Rest; Rewards; Risk Factors; Role; Signal Transduction; Stress; Structure; Testing; Training; Ventral Striatum; Vertebral column; addiction; adverse outcome; anxiety-like behavior; brain behavior; brain shape; cognitive function; emotion regulation; experience; feeding; girls; infancy; maternal stress; neurobehavioral; neurodevelopment; neuroimaging; obesity in children; postnatal; preference; prenatal experience; prevent; public health relevance; restraint; social; social stress; stimulant abuse; stressor

 DESCRIPTION (provided by applicant): Chronic social stress during childhood produces adverse outcomes on neurodevelopment and in turn deficits in socioemotional, motivational and cognitive functions. Currently, the effects of stress and resulting neurodevelopmental alterations (specifically, prefrontal cortex structural and functional connectivity with both amygdala and striatum) that impact emotional and impulse control and reward in children are poorly understood. The objective of the proposed research is to elucidate the mechanisms by which chronic social stress contributes to the over-consumption of a calorically dense diet (CDD) and how both stress and the resulting obese phenotype affect neurodevelopment in females using a rhesus monkey model. In addition, potential biological signals linking the adverse social experience and increased fat mass to neurobehavioral deficits will be examined. For this, I will investigate whether chronic postnatal exposure to a social stressor (social subordination in rhesus macaques), developmentally contributes to overconsumption of a CDD and whether the resulting obesity has a synergistic effect, further altering the developmental trajectory of brain and behavior. Female monkeys, who will be cross fostered at birth to control for the potential confounding effects of heritable factors and maternal stress during gestation, will be studied longitudinally from birth through pre-puberty (16 mo) as detailed in the aims below. In Aim 1, I will examine whether chronic social stress impairs the development of emotional and stress regulation as well as inhibitory control of behavior, leading to the emergence of emotional feeding. Emotional reactivity and impulsivity will be examined longitudinally using well-established testing paradigms. Aim 2 will examine the neurobiological underpinnings of the behavioral alterations studied in Aim 1, focusing on chronic stress-induced impairments of the developmental trajectory of prefrontal cortex (PFC) connectivity with amygdala (AMYG) and ventral striatum (nucleus accumbens: NAcc). For this, I will employ state-of-the-art longitudinal neuroimaging approaches involving Diffusion Tensor Imaging (DTI) and resting state functional connectivity Magnetic Resonance Imaging (rs-fMRI) to assess the effects of social stress on the development of structural and functional connectivity of these circuits. Finally, for Aim 3 I will test the hypothesis that stress- induced consumption of a CDD will lead to the emergence of obesity that will further impair PFC-AMYG and PFC-NAcc structural and functional connectivity and resulting behavior. This research provides an invaluable opportunity for training in behavioral neuroscience that will allow me to investigate how stress, emotional feeding, and resulting obesity adversely affect neurobehavioral development in a translational animal model for girls.

 描述（由申请人提供）：儿童时期的慢性社会压力对神经发育产生不利影响，进而导致社会情感、动机和认知功能的缺陷。目前，压力的影响和由此产生的神经发育变化（特别是前额叶皮层与杏仁核和纹状体的结构和功能连接）影响儿童的情绪和冲动控制和奖励的影响知之甚少。拟议的研究的目的是阐明慢性社会压力导致热量密集饮食（CDD）过度消费的机制，以及压力和由此产生的肥胖表型如何影响恒河猴模型女性的神经发育。此外，将检查将不良社会经历和脂肪量增加与神经行为缺陷联系起来的潜在生物信号。为此，我将调查慢性产后暴露于社会应激源（猕猴的社会从属地位），是否在发育上有助于过度消费的CDD和由此产生的肥胖是否具有协同效应，进一步改变大脑和行为的发育轨迹。将对出生时交叉饲养以控制遗传因素和妊娠期母体应激的潜在混杂效应的雌性猴进行从出生至青春期前（16个月）的纵向研究，详见下文目的。 在目标1中，我将研究慢性社会压力是否会损害情绪和压力调节以及行为抑制控制的发展，从而导致情绪喂养的出现。情绪反应性和冲动性将使用成熟的测试范式进行纵向检查。目标2将研究目标1中研究的行为改变的神经生物学基础，重点是慢性应激诱导的前额叶皮层（PFC）与杏仁核（AMYG）和腹侧纹状体（NAcc）连接的发育轨迹损伤。为此，我将采用最先进的纵向神经成像方法，包括扩散张量成像（DTI）和静息状态功能连接磁共振成像（rs-fMRI），以评估社会压力对这些电路的结构和功能连接发展的影响。最后，对于目标3，我将检验以下假设：压力诱导的CDD消耗将导致肥胖症的出现，这将进一步损害PFC-AMYG和PFC-NAcc结构和功能连接以及所产生的行为。这项研究为行为神经科学的培训提供了一个宝贵的机会，这将使我能够在女孩的转化动物模型中研究压力，情绪喂养和由此产生的肥胖如何对神经行为发育产生不利影响。