Stress and obesity synergize to impair neurobehavioral development in females

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，尤其是对女性。目前还不清楚母亲在怀孕期间所经历的社会压力是如何与她的后代所经历的产后压力协同作用产生这些表型的。重要的是，其他可能与压力源暴露相互作用影响儿童时期大脑发育的环境因素经常被忽视，最明显的是热量密集饮食（cdd）的消耗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速度，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，因为体脂增加与大脑结构改变和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是至关重要的，因为儿童肥胖率惊人，可能是由于摄入了cdd——一种与典型的低热量饮食喂养动物作为儿童模型截然不同的饮食环境。关键的生物信号可能是应激诱导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。对儿童健康和疾病的发育起源进行前瞻性研究是困难的。然而，社会饲养的恒河猴提供了一个有效的转化模型，因为社会从属关系甚至在发育过程中产生了明显的压力相关表型。该应用程序将解决四个具体目标，以测试产前母亲压力与产后社会压力相互作用的总体假设，以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。目的1将确定增加的脂肪量是否与产后社会压力相互作用，从而改变女性社会和情感行为的发展轨迹，以及前额叶相关的认知功能。利用神经影像学，Aim 2将检验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以及执行功能和自我调节的区域的连接的假设，并通过青春期过渡加速差异。Aim 3的中介分析将检验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。通过交叉培养，Aim 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，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，将提供关键信息，有助于形成临床干预和社会政策改进，以优化女孩的神经行为发育。

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.