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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.

项目总结