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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

基本信息

批准号：
9305145
负责人：
MAR M SANCHEZ
金额：
$ 69.64万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/9305145
关键词：
Address Adolescent Adult Adverse effects Affect Amygdaloid structure Animals Anti-Inflammatory Agents Anti-inflammatory Anxiety Awareness Behavior Behavioral Biological Biological Neural Networks Birth Body fat Brain Child Child health care Childhood Chronic Chronic stress Clinical Cognition Cognitive Consumption Data Development Diet Diffusion Magnetic Resonance Imaging Disease Emotional Emotional Stress Emotions Environment Environmental Risk Factor Estradiol Executive Dysfunction Exposure to Fatty acid glycerol esters Female Fostering Fright Functional Magnetic Resonance Imaging Health Hormones 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 Prospective Studies Protocols documentation Puberty Reporting Rest Risk Risk Factors Sensory Shapes Signal Transduction Social Behavior Social Policies Stress Structure Testing adverse outcome anxious behavioral impairment biobehavior brain behavior brain health cognitive function cytokine emotional behavior executive function experience girls infancy inflammatory marker innovation maternal stress metabolic phenotype neurobehavioral neurodevelopment neuroimaging obesity in children offspring postnatal prenatal prenatal stress public health relevance social social stigma social stress stressor synergism

项目摘要

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，特别是对女性而言。目前还不清楚母亲在妊娠期间经历的社会压力如何与后代经历的产后压力协同作用以产生这些表型。重要的是，其他可能与压力源相互作用相互作用从而影响儿童期大脑发育的环境因素经常被忽视，最明显的是高热量饮食（CDD）的消耗以及由此产生的代谢表型。事实上，这可能存在协同作用，因为慢性社会压力是儿童肥胖的累积风险因素。肥胖不仅可能会加快青春期的速度，而且有限的儿童数据表明，发育中的大脑很容易受到这些代谢损伤的影响，因为身体脂肪的增加与大脑结构的改变以及认知和情绪处理的缺陷有关。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，这可能是由于食用 CDD 所致——这种饮食环境与用作儿童模型的动物喂养的典型低热量饮食完全不同。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，而脂肪量的增加会加剧这种升高。在儿童中很难对健康和疾病的发育起源进行前瞻性研究。然而，社会饲养的恒河猴提供了一种有效的转化模型，因为即使在发育过程中，社会从属也会产生独特的与压力相关的表型。该应用程序将解决四个具体目标，以测试一个总体假设，即产前母亲压力与产后社会压力相互作用，改变女性从婴儿期到青春期的神经行为发育，而这些损害会因肥胖而加剧。目标 1 将确定脂肪量的增加是否与产后社会压力相互作用，从而改变女性社交和情感行为以及前额叶相关认知功能的发展轨迹。目标 2 将利用神经影像学检验这样的假设：社会压力和脂肪量增加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绪行为以及婴儿期执行功能和自我调节区域的连通性，并在青春期过渡期间加速差异。目标 3 中的中介分析将检查皮质醇和炎症标记物是否介导社会压力和脂肪量对神经行为发育受损的影响。通过交叉寄养，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，从而进一步损害神经行为发育。该项目将识别介导压力和肥胖对大脑健康和行为产生不利影响的潜在生物信号，并在此过程中提供重要信息，帮助制定临床干预措施和社会政策改进，以优化女孩的神经行为发育。