Enduring Consequences of Chronic Repeated Stress on Neuro-Metabolic Function

慢性反复压力对神经代谢功能的持久影响

• 批准号: 10464422
• 负责人: Gladys Alexis Shaw
• 金额: $ 4.41万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464422
• 关键词: ATP phosphohydrolase; Adolescence; Adolescent; Adult; Age; Age-Years; Aging; Alzheimer' s Disease; Americas; Anxiety; Brain; C57BL/6 Mouse; Cell Membrane Permeability; Chronic; Chronic stress; Classification; Cognitive; Complex; Corticosterone; Data; Dementia; Development; Diagnosis; Disease; Early Diagnosis; Electron Transport; Emotional; Environment; Estrogen Receptor beta; Estrogens; Ethanol; Event; Female; Foundations; Genes; Genetic Transcription; Genus Hippocampus; Goals; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal; Hormones; Human; Impaired cognition; Individual; Learning; Life; Link; Literature; Measurement; Measures; Mediator of activation protein; Membrane; Memory; Memory impairment; Mental Depression; Mental Health Services; Mental disorders; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Mitochondrial Matrix; Modeling; Molecular; Mood Disorders; Mus; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Oxidative Phosphorylation; Oxygen Consumption; Peripheral; Physiological; Population; Predatory Behavior; Predisposition; Preventive treatment; Production; Proteins; Protons; Rattus; Recording of previous events; Reproducibility; Respiration; Risk; Rodent; Severities; Sex Differences; Shapes; Stress; Synapses; Synaptosomes; Testing; Time; Trauma; UCP2 protein; Work; adverse childhood events; anxiety-like behavior; brain behavior; college; critical period; depressive symptoms; early life stress; emerging adult; high risk; high school; hypothalamic-pituitary-adrenal axis; instrument; male; mild cognitive impairment; mitochondrial dysfunction; mitochondrial genome; mitochondrial membrane; mitochondrial uncoupling protein; neurocognitive disorder; neurodevelopment; neuromechanism; novel; oligomycin sensitivity-conferring protein; protein expression; psychologic; relating to nervous system; sex; stressor

Project Summary While neurocognitive disorders are becoming more prevalent within America’s aging populations, mood disorders are steadily being diagnosed at younger ages each year. The positive correlation between adverse childhood experience and the development of disorders including, depression, anxiety, and Alzheimer’s disease, suggests a crucial connection between trauma and long-lasting neurological changes. Previous focus has been on the impact of early life stress and the subsequent changes in the brain, however little focus has been placed on repeated trauma that begins in, and continues throughout, the highly dynamic and unique developmental period of adolescence into early adulthood. The combination of hormonal surges and peak in more severe trauma and abuse undoubtedly shapes the neural landscape. Moreover, the aforementioned disorders demonstrate sex-specific shifts that are heavily linked to the shift in hormone concentration circulating throughout the body during this period. The classification of stress as a metabolic disorder and the strong connection between sex hormones, mitochondrial function, and sex-specific alterations in the hypothalamic-pituitary-adrenal axis following chronic stress (CS) have been topics of increased discussion. Therefore, it is of utmost importance to explore the relationship between these factors and potential mechanistic differences between the sexes. Data from the literature suggests that chronic activation of the HPA axis in male rodents alters the mitochondrial genome and may change synaptic mitochondrial respiration and mitochondrial membrane permeability. Preliminary data suggests increased mitochondrial respiration in whole brain synaptosomes of females but not males following CS. Using male and female C57Bl/6 mice subject to 15 consecutive days of chronic repeated predation (CRPS) stress during adolescence and another 15 consecutive days during early adulthood, this proposal aims to assess persistent changes within synaptic mitochondrial respiration of the hippocampus (HPC) following trauma. Mitochondrial oxidative phosphorylation will be measured from HPC synaptosomes to assess region specific stress- and sex effects. Measurement of mitochondrial ERβ and UCP2 will provide foundational evidence to begin developing a mechanism explaining these changes. The overarching goal of this proposal is to determine the effect of CRPS in the alteration of metabolic function in HPC neurons and mitochondrial Erβ and UCP2 expression in a sex- and stress- specific manner. Resulting data will support the claim that CS during this critical timepoint promotes persistent, sex- specific changes subsequently increasing the risk of psychological disorders and neurodegeneration. Understanding the link between chronic repeated trauma and subsequent alterations in both brain and behavior in adulthood may aid in the identification of high-risk individuals, aid in the early detection of cognitive decline, and assist in the development of the neural mechanisms to be used in the development of novel, preventative treatments for both mood and neurodegenerative disorders to advance mental healthcare.

项目概要 虽然神经认知障碍在美国老龄化人口中变得越来越普遍，但情绪 每年诊断出疾病的年龄都在不断趋于年轻化。不良反应之间呈正相关关系 童年经历和疾病的发展，包括抑郁、焦虑和阿尔茨海默病 疾病，表明创伤和长期神经系统变化之间存在重要联系。之前的焦点 人们一直在研究早期生活压力的影响以及随后大脑的变化，但是很少有人关注 遭受反复的创伤，这种创伤始于并贯穿始终，高度动态和独特 青春期到成年早期的发育时期。荷尔蒙激增和高峰的结合 更严重的创伤和虐待无疑会塑造神经景观。此外，前述 疾病表现出性别特异性的变化，与激素浓度的变化密切相关 在此期间循环到全身。压力作为代谢紊乱的分类和 性激素、线粒体功能和性别特异性改变之间存在密切联系 慢性应激（CS）后的下丘脑-垂体-肾上腺轴一直是人们讨论最多的话题。 因此，探讨这些因素与潜力之间的关系至关重要。 性别之间的机械差异。文献数据表明，慢性激活 雄性啮齿动物的 HPA 轴改变线粒体基因组，并可能改变突触线粒体呼吸 和线粒体膜通透性。初步数据表明线粒体呼吸增加 CS 后女性而非男性的全脑突触体。使用雄性和雌性 C57Bl/6 小鼠 在青春期和另一个时期遭受连续 15 天的慢性重复捕食 (CRPS) 压力 该提案旨在评估成年早期的连续 15 天突触内的持续变化 创伤后海马体（HPC）的线粒体呼吸。线粒体氧化磷酸化 将从 HPC 突触体中测量，以评估区域特定的压力和性别影响。测量 线粒体 ERβ 和 UCP2 将为开始开发解释机制提供基础证据 这些变化。该提案的总体目标是确定 CRPS 在改变 HPC 神经元的代谢功能以及性别和应激特异性的线粒体 Erβ 和 UCP2 表达 方式。由此产生的数据将支持这样的说法：CS 在这个关键时间点促进持久的、性- 随后的特定变化会增加心理障碍和神经退行性疾病的风险。 了解慢性反复创伤与随后的大脑和大脑变化之间的联系 成年期的行为可能有助于识别高危个体，有助于早期发现认知障碍 衰退，并协助神经机制的发展，用于开发新的、 针对情绪和神经退行性疾病的预防性治疗，以促进心理保健。