NEUROPATHOLOGICAL SIGNATURES CONNECTING EARLY-LIFE TRAUMA TO COMPULSIVE EATING BEHAVIOR AND OBESITY

童年创伤会增加体重严重增加和成年后肥胖的风险。然而，暴露在早期生活创伤中的个体肥胖风险增加的途径仍然知之甚少。我们实验室的临床前发现支持这样的观点，即皮质结构变化和行为障碍，包括饮食行为紊乱的存在，可能是成人肥胖风险增加的原因。这项研究的具体目标是确定将早期生活创伤与晚年异常饮食行为联系起来的因果路径。我们强有力的初步数据表明：1)早期生活创伤和肥胖饮食暴露导致内侧前额叶皮质(MPFC)显著的结构损伤，2)早期暴露于这种肥胖环境增加了食物摄入量和肥胖样表型，3)这些环境条件改变了生长因子NeuRegin-1(NRG1)的水平和信号。基于这些强大的初步数据，我们假设，前额叶皮质NRG1信号的过度激活有助于早期创伤应激对树突棘丢失、突触密度和异常的皮质网络成熟和摄食模式的影响，促进成年期的快速体重增加和肥胖表型。我们建议追求两个特定的目标，以确定早期环境逆境影响的神经底物和分子机制：1)我们将使用翻译和创新扩散成像模式(NODI)和基于SV2A的正电子发射断层扫描(PET)来确定早期生活创伤对mPFC亚区微结构和突触密度的纵向影响；2)确定早期生活创伤削弱最佳神经营养支持，导致摄食行为异常控制(摄入量增加和食物偏好)的分子机制。这一建议将产生重大的积极影响，因为它将识别创伤暴露的早期和微小的微结构脆弱性和神经成像生物标记物。此外，这项探索性提案中概述的实验将有助于加强我们对潜在的趋同神经病理学和将早期生活创伤与摄食行为障碍和肥胖联系起来的分子途径的理解。更好地了解这些适应可能有助于确定预防和治疗童年逆境对身心健康结果的长期影响的新机会。

Childhood trauma heightens the risk of severe weight gain and adult obesity. However, the pathways for the increased risk of obesity in individuals exposed to early-life trauma remain poorly understood. Preclinical findings from our laboratory support the notion that cortical structural alterations and behavioral impairments, including the presence of disordered eating behavior, may account for the added risk of adult obesity. The specific goal of this study is to identify causal pathways connecting early-life trauma to aberrant eating behaviors later in life. Our strong preliminary data indicate that: 1) early-life trauma and exposure to an obesogenic diet results in marked structural impairments in the medial prefrontal cortex (mPFC), 2) early-life exposure to this obesogenic environment increases food intake and obesity-like phenotypes, and 3) these environmental conditions alter the levels and signaling of the growth factor neuregulin-1 (NRG1). Based on this strong preliminary data, we hypothesize that overactivation of NRG1 signaling in the prefrontal cortex contributes to the effects of early-life traumatic stress on dendritic spine loss, synaptic density, and aberrant cortical network maturation and feeding patterns, promoting rapid weight gain and obesogenic phenotypes during adulthood. We propose to pursue two Specific Aims to identify neural substrates and molecular mechanisms impacted by early-life environmental adversities: 1) we will use translational and innovative diffusion imaging modalities (NODDI) and SV2A-based positron emission tomography (PET) to determine the longitudinal effects of early-life trauma on mPFC subfield microstructure and synaptic densities; 2) identify molecular mechanisms by which early-life trauma attenuates optimal neurotrophic support, resulting in aberrant control of feeding behaviors (increased intake and palatable food preference). This proposal will have a significant positive impact because it will identify early and subtle microstructural vulnerabilities and neuroimaging biomarkers to trauma exposure. Furthermore, the experiments outlined in this exploratory proposal will contribute to enhancing our understanding of the underlying convergence neuropathology and molecular pathways linking early-life trauma to disordered feeding behaviors and obesity. Having a better understanding of these adaptations may contribute to the identification of new opportunities to prevent and treat the long-term impact of childhood adversities on physical and mental health outcomes.