Stress and obesity synergize to impair neurobehavioral development in females

压力和肥胖协同损害女性神经行为发育

• 批准号: 8697088
• 负责人: MAR M SANCHEZ
• 金额: $ 70.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697088
• 关键词: Address; Adolescent; Adult; Adverse effects; Affect; Amygdaloid structure; Animal Feed; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Awareness; Behavior; Behavior assessment; Behavioral; Biological; Biological Neural Networks; Birth; Body fat; Brain; Child; Child health care; Childhood; Chronic; Clinical; Cognition; Cognitive; Consumption; Data; Development; Diet; Diffusion Magnetic Resonance Imaging; Disease; Emotional; Emotional Stress; Emotions; Environment; Environmental Risk Factor; Estradiol; Exposure to; Fatty acid glycerol esters; Female; Fostering; Fright; Functional Magnetic Resonance Imaging; Health; Health behavior; Hormones; Housing; Hydrocortisone; Impaired cognition; Impairment; Inflammatory; Informal Social Control; Intervention; Longitudinal Studies; Macaca mulatta; Mediating; Mediation; Metabolic; Modeling; Monkeys; Mothers; Motivation; Obesity; Outcome; Overweight; Pathway interactions; Peripheral; Phenotype; Prefrontal Cortex; Pregnancy; Process; Prospective Studies; Protocols documentation; Puberty; Reporting; Rest; Risk; Risk Factors; Sensory Process; Shapes; Signal Transduction; Social Policies; Stress; Structure; Testing; adverse outcome; behavioral impairment; cognitive function; cytokine; executive function; experience; girls; infancy; inflammatory marker; innovation; maternal stress; neurobehavioral; neurodevelopment; neuroimaging; obesity in children; offspring; postnatal; prenatal; prenatal stress; public health relevance; social; social stigma; social stress; stressor

DESCRIPTION (provided by applicant): Studies of both animals and children show that postnatal stress may have lasting effects on brain structure and function, resulting in behavioral and cognitive impairments, particularly for females. It is also unclear how social stress experienced by the mother during gestation synergizes with postnatal stress experienced by her offspring to produce these phenotypes. Importantly, other environmental factors that may interact with stressor exposure to affect brain development during childhood are frequently overlooked, most notably the consumption of calorically dense diets (CDDs) and the resulting metabolic phenotype. Indeed, there is likely a synergy, as chronic social stress is a cumulative risk factor for childhood obesity. Not only may obesity accelerate the tempo of puberty but limited data in children suggest the developing brain is vulnerable to these metabolic insults, as increased body fat is associated with altered brain structure and deficits in cognition and emotional processing. Understanding the impact of stress and obesity on neurodevelopment is critically relevant, given alarming rates of obesity in children, likely due to the consumption of CDDs - a dietary environment quite unlike the typical low caloric diets fed animals used as models for children. Key biological signals could be stress-induced elevations in cortisol and proinflammatory cytokines that are exacerbated by increased fat mass. Prospective studies of the developmental origins of health and disease are difficult to do in children. However, socially housed rhesus monkeys provide an effective translational model, as social subordination produces distinct stress-related phenotypes even during development. This application will address four specific aims to test the overarching hypothesis that prenatal maternal stress interacts with post natal social stress to alter female neurobehavioral development from infancy through puberty and these impairments are exacerbated by obesity. Aim 1 will determine whether increased fat mass interacts with postnatal social stress to alter developmental trajectories of female social and emotional behavior, as well as prefrontal-related cognitive function. Using neuroimaging, Aim 2 will test the hypothesis that social stress and increased fat mass will synergize to alter structural and functional development of the prefrontal cortex (PFC) and its connectivity with regions regulating social and emotional behaviors as well as executive function and self-regulation from infancy, with differences accelerating through the pubertal transition. Mediation analysis in Aim 3 will examine whether cortisol and inflammatory markers mediate the effects of social stress and fat mass on impaired neurobehavioral development. Using cross-fostering, Aim 4 will determine how maternal stress during gestation synergizes with postnatal social stress and obesity to further compromise neurobehavioral development. The project will identify potential biological signals that mediate the adverse effects of stress ad obesity on brain health and behavior and, in doing so, will provide crucial information that will help shape clinical interventions and social policy improvement to optimize neurobehavioral development in girls.

描述（由申请人提供）：对动物和儿童的研究表明，产后压力可能对大脑结构和功能产生持久影响，导致行为和认知障碍，特别是女性。目前还不清楚母亲在怀孕期间所经历的社会压力如何与其后代所经历的产后压力协同产生这些表型。重要的是，其他环境因素，可能会相互作用的压力暴露影响大脑发育在儿童时期经常被忽视，最显着的热量密集饮食（CDDs）的消费和由此产生的代谢表型。事实上，这可能是一种协同作用，因为长期的社会压力是儿童肥胖的累积风险因素。肥胖不仅可能加速青春期的克里思，而且儿童的有限数据表明，发育中的大脑容易受到这些代谢损伤，因为身体脂肪增加与大脑结构改变以及认知和情感处理缺陷有关。了解压力和肥胖对神经发育的影响至关重要，因为儿童肥胖率惊人，可能是由于消费CDDs -饮食环境与用作儿童模型的典型低热量饮食喂养的动物完全不同。关键的生物信号可能是压力引起的皮质醇和促炎细胞因子的升高，这些升高会因脂肪量增加而加剧。对健康和疾病的发展起源的前瞻性研究很难在儿童中进行。然而，社会圈养的恒河猴提供了一个有效的翻译模型，因为社会从属关系甚至在发育过程中也会产生不同的压力相关表型。本申请将解决四个具体目标，以测试总体假设，产前母亲压力与纳塔尔社会压力相互作用，改变女性神经行为发育从婴儿期到青春期，这些障碍是由肥胖加剧。目的1将确定增加的脂肪量是否与产后社会压力相互作用，以改变女性社会和情感行为的发展轨迹，以及前额相关的认知功能。使用神经成像，目标2将测试假设，即社会压力和增加的脂肪量将协同改变前额叶皮层（PFC）的结构和功能发育及其与调节社会和情感行为的区域的连接以及执行功能和自我调节从婴儿期开始，通过青春期过渡加速差异。目标3中的中介分析将检查皮质醇和炎症标志物是否介导社会压力和脂肪量对受损神经行为发育的影响。利用交叉培养，目标4将确定妊娠期间的母亲压力如何与产后社会压力和肥胖协同作用，以进一步损害神经行为发育。该项目将确定潜在的生物信号，介导压力和肥胖对大脑健康和行为的不利影响，并在此过程中提供关键信息，帮助制定临床干预措施和社会政策改善，以优化女孩的神经行为发育。