Stress and obesity synergize to impair neurobehavioral development in females

描述(申请人提供)：对动物和儿童的研究表明，出生后的压力可能会对大脑结构和功能产生持久的影响，导致行为和认知障碍，特别是对女性。母亲在怀孕期间经历的社会压力如何与她的后代经历的出生后压力协同产生这些表型也不清楚。重要的是，其他环境因素可能与应激源暴露相互作用，影响儿童时期的大脑发育，但往往被忽视，最明显的是高热量饮食(CDD)的消费和由此产生的代谢表型。事实上，这可能是一种协同效应，因为慢性社会压力是儿童肥胖的累积风险因素。肥胖不仅可能加速青春期的节奏，而且有限的儿童数据表明，发育中的大脑很容易受到这些新陈代谢的侮辱，因为体脂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，因为儿童肥胖率令人震惊，可能是由于食用CDD-一种与典型的低热量饮食完全不同的饮食环境，这些动物被用作儿童的模型。关键的生物信号可能是压力诱导的皮质醇和促炎细胞因子的升高，而脂肪质量的增加会加剧这些细胞因子的增加。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，社会寄养恒河猴提供了一个有效的转换模型，因为即使在发育过程中，社会从属关系也会产生不同的压力相关表型。这项应用将解决四个具体目标，以检验主要假设，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。目的1将确定肥胖增加是否与出生后的社会应激相互作用，从而改变女性社会和情感行为的发育轨迹，以及与前额叶相关的认知功能。利用神经成像，Aim 2将测试这一假设，即社会压力和增加的脂肪量将协同改变前额叶皮质(PFC)的结构和功能发育，以及它与调节社会和情绪行为以及执行功能和自我调节的区域的连接，从婴儿时期开始，差异会在青春期过渡期间加速。目标3中的中介分析将检验皮质醇和炎症标记物是否在社会压力和脂肪量对神经行为发育受损的影响中起中介作用。利用交叉养育，目标4将确定怀孕期间的母亲压力如何与出生后的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，以调解压力和肥胖对大脑健康和行为的不利影响，并通过这样做，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.