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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要尽管神经认知障碍在美国的老龄化中变得越来越普遍，但情绪疾病每年都在稳定地被诊断出来。广告之间的正相关童年经验和疾病的发展，包括抑郁症，动画和阿尔茨海默氏症疾病，表明创伤与持久神经系统变化之间存在至关重要的联系。以前的重点已经对早期生活压力的影响和随后的大脑变化的影响，但是重点很少被置于重复的创伤上，开始并持续到整个过程中，高度动态和独特青少年成年早期的发展时期。荷尔蒙潮流和峰值的组合毫无疑问，更严重的创伤和虐待塑造了神经元景观。而且，这一理由疾病表明性别特定的转变与激素浓度的转移密切相关在此期间，整个身体循环。压力分类为代谢障碍和性恐怖，线粒体功能和性别特定的变化之间的紧密联系慢性应激（CS）后下丘脑 - 垂体 - 肾上腺轴已成为讨论增加的主题。因此，探索这些因素与潜在之间的关系至关重要性别之间的机械差异。来自文献的数据表明，长期激活雄性啮齿动物中的HPA轴改变了线粒体基因组，可能会改变突触线粒体呼吸和线粒体膜的通透性。初步数据表明，线粒体呼吸增加 cs之后，女性的全脑突触体，但不是男性。使用雄性和雌性C57BL/6小鼠在青少年和另一个在成年初期，该提案连续15天，旨在评估突触中的持续变化创伤后海马（HPC）的线粒体呼吸。线粒体氧化磷酸化将从HPC突触体测量以评估区域特异性应激和性别影响。测量线粒体ERβ和UCP2将提供基本的证据，以开始开发一种解释机制这些变化。该提案的总体目标是确定CRP对改变的影响性别和应力特异性的HPC神经元和线粒体ERβ和UCP2表达的代谢功能方式。由此产生的数据将支持以下主张：在此关键时间点期间CS促进持续性，性别 - 特定的变化随后增加了心理疾病和神经退行性的风险。了解慢性重复创伤与随后大脑和随后的改变之间的联系成年时的行为可能有助于识别高风险个体，有助于早期发现认知下降，并有助于开发用于开发新颖的神经力学的发展，对情绪和神经退行性疾病的预防性治疗，以促进心理保健。