Identification & Prevention of Developmental Myelin Misregulation in PTSD

鉴别

• 批准号: 8103728
• 负责人: Daniela KAUFER
• 金额: $ 9.37万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103728
• 关键词: Adrenal Glands; Adult; Adverse event; Anxiety; Behavior; Behavioral; Brain; Caring; Cells; Cognitive; Development; Environment; Genes; Glucocorticoids; Hippocampus (Brain); Hormones; Intervention; Life; Light; Longevity; Mental Depression; Mental disorders; Molecular; Myelin; Neonatal; Neurons; Output; Pattern; Performance; Post-Traumatic Stress Disorders; Predisposition; Prevention; Production; Psychopathology; Reporting; Schizophrenia; Stress; Suicide; Supporting Cell; Testing; Time; acute stress; base; behavioral impairment; cognitive function; early experience; gene therapy; innovation; maternal separation; myelination; neural precursor cell; prevent; pup; response; tool; transcription factor; vector; white matter

DESCRIPTION (provided by applicant): Changes in white matter have been reported in depression, schizophrenia, and post- traumatic stress disorder (PTSD) and suicide, suggesting that altered myelination may be a new mechanism by which psychopathologies emerge. We found that stress and the adrenal stress hormones, glucocorticoids (GC), induce Neural Precursor Cells in the adult hippocampus to an oligodendrogenic fate, thereby increasing myelin production capacity. We have also demonstrated increased myelination capacity in the hippocampus of pups subjected to adverse parental care. Here, we hypothesize that early adverse experiences increase myelination across the lifespan, altering development of the brain environment and increasing susceptibility to mental illness including PTSD and depression. We propose to examine the effects that neonatal stress and adverse parental care have on long-lasting changes on white matter patterning across the lifespan, using an integrated approach that correlates molecular/cellular analysis with behavioral outputs. In specific aims 1-2, we will document, at the cellular level, changes in myelination and oligodendrogenesis after early life maternal separation or low maternal care, and analyze the underpinnings of myelination at the molecular level by qPCR of the transcription factors involved in cell fate choice, and myelin-related genes. Furthermore, we will correlate developmental white matter patterning with vulnerability to PTSD in response to acute stress in adulthood. In specific aim 3, we will use anti-GC gene intervention vectors to try to prevent misdevelopment of the white matter when delivered in early life, or mitigate persistent white matter dysregulation when delivered in adulthood. In specific aim 4, we will expand these cellular-level analyses to the behavioral level by testing for depression/anxiety behavior and hippocampus-dependent cognitive performance in each experimental group. Together, these aims will give us a comprehensive picture of the development of altered white matter patterning after early adverse experience, ranging from quantification of myelin and oligodendrogenesis at different developmental time points to ultimate effects in impaired behavior and cognitive function. This application is innovative in (1) focusing on white matter support cells, rather than neurons, as a developmental basis for mental illness and (2) using interdisciplinary, integrative approaches to explore the developmental basis of mental illness. This project aims to examine whether adverse early experiences exert long-lasting changes on oligodendrogenesis and myelination across the lifespan, and render vulnerability to development of mental illness such as post-traumatic stress disorder and depression. Anti-glucocorticoids genetic therapies are employed as tools to prevent or reverse these effects. This application is innovative, as it sheds light on a generally unexplored issue-the persistent dysregulation of white matter by early adverse experience, and how this contributes to the development of brain malfunction in adulthood, specifically in the context of mental illness.

描述（由申请人提供）：抑郁症，精神分裂症和创伤后应激障碍（PTSD）和自杀中已经报告了白质的变化，这表明髓鞘变化可能是一种新机制，可以通过这种机制出现。我们发现，应激和肾上力胁迫激素，糖皮质激素（GC），诱导成年海马中的神经前体细胞，从而提高髓磷脂生产能力。我们还证明，受到不良父母护理的幼崽海马的髓鞘素化能力提高。在这里，我们假设早期的不良经历会增加整个生命周期的髓鞘形成，改变了大脑环境的发展，并增加了对精神疾病（包括PTSD和抑郁症）的敏感性。我们建议使用将分子/细胞分析与行为输出相关联的综合方法来检查新生儿应力和不良父母护理对整个生命周期中白质模式的长期变化的影响。在特定的目标1-2中，我们将在细胞水平上记录早期产妇分离或低产妇护理后的髓鞘形成和少突胶质发生的变化，并通过qPCR分析骨髓水平上髓鞘化的基础，这些转录因子涉及细胞命运选择的转录因子和髓磷脂相关基因。此外，我们将将发育性的白质模式与成年后的急性压力响应于PTSD的脆弱性相关联。在特定的目标3中，我们将使用抗GC基因干预媒介来试图防止早期交付时误解白质，或者在成年期交付时减轻持续的白质失调。在特定目标4中，我们将通过测试每个实验组的抑郁/焦虑行为和海马依赖性认知表现，将这些细胞级别的分析扩展到行为水平。共同，这些目标将使我们全面了解早期不良经历后白质模式变化的发展，从不同发育时间点的髓磷脂和少突根发生到对行为受损和认知功能的最终影响。 （1）专注于白质支持细胞而不是神经元作为精神疾病的发育基础，以及（2）使用跨学科的综合方法探索精神疾病的发育基础。该项目旨在研究不利的早期经历是否会在整个生命周期内对少突义生成和髓鞘产生持久的变化，并使诸如创伤后应激障碍和抑郁症等精神疾病的发展变得脆弱。抗葡萄糖皮质激素基因疗法被用作预防或逆转这些影响的工具。该应用具有创新性，因为它阐明了一个普遍尚未开发的问题 - 通过早期不良经历对白质的持续失调，以及这如何有助于成年后脑失功能的发展，特别是在精神疾病的背景下。