Identification & Prevention of Developmental Myelin Misregulation in PTSD

描述（由申请人提供）：在抑郁症、精神分裂症、创伤后应激障碍（PTSD）和自杀中已经报道了白色物质的变化，这表明髓鞘形成的改变可能是精神病理学出现的一种新机制。我们发现，压力和肾上腺应激激素，糖皮质激素（GC），诱导神经前体细胞在成年海马少突胶质细胞的命运，从而增加髓鞘生产能力。我们还证明了增加髓鞘形成能力在海马的幼崽受到不利的父母照顾。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（包括创伤后应激障碍和抑郁症）的易感性。我们建议检查新生儿的压力和不利的父母照顾的影响，在整个生命周期的白色物质图案的持久变化，使用一个综合的方法，相关的分子/细胞分析与行为输出。在具体目标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神经发生的变化，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在分子水平上分析髓鞘形成的基础。此外，我们将把发育中的白色物质模式与成年后对急性压力的反应中对PTSD的脆弱性联系起来。在具体目标3中，我们将使用抗GC基因干预载体来尝试防止在生命早期分娩时白色物质的错误发育，或减轻在成年期分娩时持续的白色物质失调。在具体目标4中，我们将通过测试每个实验组的抑郁/焦虑行为和校园依赖性认知表现，将这些细胞水平的分析扩展到行为水平。总之，这些目标将给我们一个全面的图片改变白色物质图案的发展后，早期不良的经验，从量化的髓鞘和少突胶质细胞在不同的发展时间点的最终影响受损的行为和认知功能。该应用的创新之处在于：（1）关注白色支持细胞而不是神经元，作为精神疾病的发育基础;（2）使用跨学科、综合方法来探索精神疾病的发育基础。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神经发育和髓鞘形成产生长期的变化，并使其容易患上精神疾病，如创伤后应激障碍和抑郁症。抗糖皮质激素基因疗法被用作预防或逆转这些效应的工具。这种应用是创新的，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色物质的持续失调，以及这如何导致成年后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.