Enduring Consequences of Chronic Repeated Stress on Neuro-Metabolic Function

项目摘要 虽然神经认知障碍在美国老龄化人口中越来越普遍，但情绪 每年都有越来越多的年轻人被诊断出患有疾病。不利因素之间的正相关 童年经历和疾病的发展，包括抑郁症，焦虑症和阿尔茨海默氏症 疾病，表明创伤和持久的神经系统变化之间的重要联系。先前焦点 一直是对早期生活压力的影响和随后的大脑变化，但很少关注 被放在反复的创伤，开始，并继续贯穿始终，高度动态和独特的 青春期到成年早期的发展阶段。荷尔蒙激增和高潮的结合 更严重的创伤和虐待无疑会塑造神经系统的面貌。此外，上述 这些疾病表现出与激素浓度变化密切相关的性别特异性变化， 在这段时间里，它在体内循环。压力作为一种代谢紊乱的分类和 性激素，线粒体功能和性别特异性改变之间的密切联系， 慢性应激（CS）后下丘脑-垂体-肾上腺轴已成为越来越多的讨论主题。 因此，探讨这些因素与潜力之间的关系至关重要 两性之间的机械差异。来自文献的数据表明， 雄性啮齿动物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， CS后雌性而非雄性的全脑突触体。使用雄性和雌性C57 B1/6小鼠 在青春期受到连续15天的慢性重复捕食（CRPS）压力， 在成年早期连续15天，该提案旨在评估突触内的持续变化， 线粒体呼吸的海马（HPC）创伤后。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效应。测量 线粒体ERβ和UCP 2的表达将为开始研究解释 这些变化。本提案的总体目标是确定CRPS在改变 HPC神经元的代谢功能和线粒体Erβ和UCP 2的表达在性别和应激特异性 方式所得数据将支持CS在此关键时间点促进持续性、性- 特定的变化，随后增加心理障碍和神经退行性变的风险。 了解慢性重复性创伤与随后的大脑和脑组织改变之间的联系， 成年期的行为可能有助于识别高风险个体，有助于早期发现认知障碍， 下降，并协助神经机制的发展，用于开发新的， 情绪和神经退行性疾病的预防性治疗，以促进心理健康。

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.