Effects of stress and obesity on neurobehavioral development of rhesus macaques

 描述(申请人提供)：儿童时期的慢性社交压力会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，应激和由此引起的神经发育变化(特别是前额叶皮质与杏仁核和纹状体的结构和功能连接)对儿童情绪和冲动控制以及奖励的影响尚不清楚。这项拟议的研究的目的是通过恒河猴模型阐明慢性社会压力导致过量摄入高热量饮食(CDD)的机制，以及压力和由此产生的肥胖表型如何影响雌性猕猴的神经发育。此外，还将研究将不良社会经历和脂肪增加与神经行为缺陷联系起来的潜在生物信号。为此，我将调查出生后长期暴露于社会压力源(猕猴的社会从属关系)是否在发育上导致CDD的过度消费，以及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。雌性猴子将在出生时被交叉寄养，以控制遗传因素和怀孕期间母亲压力的潜在混杂影响，将从出生到青春期前(16个月)进行纵向研究，详细说明如下目标。在目标1中，我将研究慢性社会压力是否损害情绪和压力调节的发展以及对行为的抑制控制，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例进行纵向测试。目的2将研究在目标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质(PFC)与杏仁核(AMYG)和腹侧纹状体(伏隔核：NACC)连接的发育轨迹的损害。为此，我将使用最先进的纵向神经成像方法，包括扩散张量成像(DTI)和静息状态功能连通性磁共振成像(RS-fMRI)，以评估社会应激对这些电路结构和功能连通性发展的影响。最后，对于目标3，我将测试一个假设，即压力诱导的CDD消费将导致肥胖的出现，而肥胖将进一步损害PFC-AMYG和PFC-NAcc的结构和功能连接以及由此产生的行为。这项研究为行为神经科学的培训提供了宝贵的机会，使我能够在女孩的翻译动物模型中调查压力、情绪喂养和由此导致的肥胖是如何对神经行为发育产生不利影响的。

 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.