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

将早年创伤与强迫性饮食行为和肥胖联系起来的神经病理学特征

• 批准号: 10339424
• 负责人: Johnny Davis Figueroa
• 金额: $ 19.66万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339424
• 关键词: Address; Adult; Attenuated; Behavior; Behavioral; Binge Eating; Brain; Brain region; Child; Child Abuse; Clinical; Data; Decision Making; Dendrites; Dendritic Spines; Development; Diet; Diffusion; Disease; Early-life trauma; Eating; Eating Behavior; Eating Disorders; Environment; Environmental Risk Factor; Enzymes; ErbB4 gene; Etiology; Exposure to; Fatty acid glycerol esters; Feeding Patterns; Feeding behaviors; Food Preferences; Functional disorder; Funding; Goals; Growth Factor; Histologic; Human; Impairment; Individual; Inflammatory; Intake; Investigation; Laboratories; Life; Life Cycle Stages; Life Style; Link; Long-Term Effects; Maintenance; Medial; Mediating; Mental Health; Modeling; Molecular; Monitor; NRG1 gene; Necrosis; Neuregulin 1; Neurobiology; Neuronal Plasticity; Obesity; Outcome; Overweight; Palate; Pathway interactions; Persons; Pharmacology; Phenotype; Play; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Prevention; Process; Protein Tyrosine Kinase; Reaction; Research Personnel; Risk; Risk Factors; Role; Secure; Signal Transduction; Structural defect; Structure; Synapses; TNF-alpha converting enzyme; Techniques; Testing; Therapeutic; Trauma; Treatment Efficacy; Underrepresented Populations; United States National Institutes of Health; Vertebral column; Weight Gain; adult obesity; base; behavioral impairment; childhood adversity; density; dietary; early detection biomarkers; early life adversity; early life exposure; emotion regulation; epidemiology study; excessive weight gain; experience; experimental study; genetic approach; imaging modality; improved; in vivo; individualized prevention; innovation; multimodality; neurobiological mechanism; neuroimaging; neuroimaging marker; neuroinflammation; neuropathology; novel; obesity development; obesity in children; obesity prevention; obesity risk; obesogenic; pediatric trauma; physical conditioning; pre-clinical; preclinical study; preference; prevent; rapid weight gain; receptor; relating to nervous system; response; restraint; sugar; synaptogenesis; translational study; trauma exposure; traumatic event; traumatic stress

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.

童年创伤会增加体重增加和成年肥胖的风险。然而，对于暴露于早期生活创伤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研究结果支持这样一种观点，即皮质结构改变和行为障碍，包括饮食紊乱行为的存在，可能是成年人肥胖风险增加的原因。本研究的具体目标是确定早期生活创伤与以后生活中异常饮食行为之间的因果关系。我们强大的初步数据表明：1)早期创伤和暴露于致肥性饮食会导致内侧前额叶皮层（mPFC）明显的结构损伤；2)早期暴露于这种致肥性环境会增加食物摄入量和肥胖样表型；3)这些环境条件会改变生长因子神经调节蛋白1 （NRG1）的水平和信号传导。基于这些强有力的初步数据，我们假设前额叶皮层NRG1信号的过度激活有助于早期生活创伤应激对树突棘丧失、突触密度、异常皮层网络成熟和喂养模式的影响，促进成年期体重快速增加和肥胖表型。我们提出了两个特定的目标来确定受早期环境逆境影响的神经基质和分子机制：1)我们将使用翻译和创新扩散成像模式（NODDI）和基于sv2的正电子发射断层扫描（PET）来确定早期创伤对mPFC子场微观结构和突触密度的纵向影响；2)确定早期创伤削弱最佳神经营养支持的分子机制，从而导致摄食行为的异常控制（摄入量增加和美味食物偏好）。该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妙的微观结构脆弱性和神经成像生物标志物。此外，本探索性提案中概述的实验将有助于增强我们对早期创伤与进食行为紊乱和肥胖之间的潜在趋同神经病理学和分子途径的理解。更好地了解这些适应可能有助于确定新的机会，以预防和治疗童年逆境对身心健康结果的长期影响。