Identification & Prevention of Developmental Myelin Misregulation in PTSD

描述（由申请人提供）：据报道，抑郁症、精神分裂症、创伤后应激障碍（PTSD）和自杀中白质的变化，表明髓鞘形成的改变可能是精神病理出现的新机制。我们发现，应激和肾上腺应激激素糖皮质激素（GC）可诱导成年海马神经前体细胞发生少突分化，从而增加髓磷脂的生产能力。我们也证明了受到不良亲代照顾的幼崽海马的髓鞘形成能力增加。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，改变大脑环境的发育，增加对精神疾病的易感性，包括创伤后应激障碍和抑郁症。我们建议使用一种将分子/细胞分析与行为输出相关联的综合方法，研究新生儿压力和不良亲代照顾对整个生命周期中白质模式的长期变化的影响。在具体的目标1-2中，我们将在细胞水平上记录早期母亲分离或低母亲护理后髓鞘形成和少突胶质发生的变化，并通过参与细胞命运选择的转录因子和髓鞘相关基因的qPCR分析分子水平上髓鞘形成的基础。此外，我们将把发育中的白质模式与成年期对急性应激的创伤后应激障碍的易感性联系起来。在具体目标3中，我们将使用抗gc基因干预载体，试图防止早期分娩时白质发育不良，或减轻成年后分娩时白质持续失调。在具体目标4中，我们将通过测试每个实验组的抑郁/焦虑行为和海马体依赖认知表现，将这些细胞水平的分析扩展到行为水平。总之，这些目标将为我们提供早期不良经历后白质模式改变发展的全面图景，从不同发育时间点髓磷脂和少突胶质形成的量化到行为和认知功能受损的最终影响。这项应用的创新之处在于(1)将重点放在白质支持细胞，而不是神经元，作为精神疾病的发展基础；(2)使用跨学科、综合的方法来探索精神疾病的发展基础。该项目旨在研究不良的早期经历是否会在整个生命周期中对少突胶质形成和髓鞘形成产生长期的影响，并使其易患创伤后应激障碍和抑郁症等精神疾病。抗糖皮质激素基因疗法被用作预防或逆转这些影响的工具。这一应用具有创新性，因为它揭示了一个普遍未被探索的问题——早期不良经历导致的白质持续失调，以及这如何导致成年期大脑功能障碍的发展，特别是在精神疾病的背景下。

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.