Individual Variation in Effects of Traumatic Stress on Gray Matter Myelin

创伤应激对灰质髓磷脂影响的个体差异

• 批准号: 10337050
• 负责人: Daniela KAUFER
• 金额: $ 68.4万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-11 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337050
• 关键词: Acute; Adult; Affect; Amygdaloid structure; Animal Model; Animals; Anterior; Area; Behavior; Brain; Brain imaging; Confounding Factors (Epidemiology); Data; Development; Dorsal; Exposure to; Fright; Functional Magnetic Resonance Imaging; Hippocampus (Brain); Human; Image; Insula of Reil; Learning; Life; Measures; Mediator of activation protein; Modeling; Myelin; Neuronal Plasticity; Oligodendroglia; Pattern; Post-Traumatic Stress Disorders; Prefrontal Cortex; Psychometrics; Rattus; Research; Research Domain Criteria; Rodent; Role; Secondary to; Severities; Stress; Structure; Symptoms; Synapses; Testing; Trauma; Viral; Virus; axonal sprouting; behavior measurement; behavioral response; brain abnormalities; density; dentate gyrus; design; emerging adult; environmental stressor; experience; exposed human population; fear memory; gray matter; human model; human subject; improved; individual variation; innovation; myelination; novel; overexpression; post-trauma; response; translational model; trauma exposure; traumatic stress

PROJECT SUMMARY/ABSTRACT This research will examine maladaptive myelination as a potential mechanism underpinning the structural and functional brain abnormalities associated with exposure to traumatic stress. Specifically, we will explore the mechanisms behind persistent sensitivity to acute threat (“fear”: RDoC domain) arising from traumatic stress during early adulthood. Myelination most likely evolved to improve conduction velocity but in gray matter (GM), it reduces axonal sprouting, synaptic density, and neuroplasticity. Exciting recent findings have shown that myelin development in both cortical and subcortical gray matter is highly plastic and strongly influenced by new experiences and learning, even during adult life. Importantly, myelin-forming oligodendrocytes are sensitive to environmental stressors and therefore may provide a novel mechanism by which aberrant structural and functional changes arise in the brain. Human brain imaging data from our labs show that subjects with a range of PTSD symptoms secondary to adult trauma exposure have increased myelin content in the hippocampal (HP), frontal, and temporal GM. Importantly, myelin content predicted symptom severity over and above potential confounding variables. Furthermore, we found that adult traumatic stress exposure in rodents produces an increase in oligodendrocytes (OGs) and myelin content in the dentate gyrus (DG), a GM structure. Similar to human subjects, our preliminary data show that symptom severity (fear score) in rats is significantly correlated with DG OGs and myelin content. Overall, these findings provide a translational model to better understand the mechanisms of oligodendrocyte and myelin plasticity in the human. In this proposal, we will test the hypothesis that traumatic stress exposure during adulthood leads to increased myelination in cortical and subcortical GM in regions critical for fear memory. Specifically, we expect to see this increased myelination only in those that subsequently become sensitive to acute threat following stress exposure. Additionally, we hypothesize that increased myelination will constrain the proper functioning of the major intrinsic functional connectivity (IFC) networks. This integrated animal-human design enables an innovative multilevel and causal exploration. Additionally, we focus on a novel role for myelin plasticity in the adult brain as a mediator of trauma-induced acute threat symptoms. Aim 1 is focused on the question of whether hippocampal gray matter myelination predict post-trauma sensitivity to acute threat. Aim 2 is focused on the question of whether the effects of trauma exposure on cortical and subcortical GM myelination predict network connectivity and fear memory.

项目概要/摘要 这项研究将研究适应不良髓鞘形成作为支撑结构和神经元的潜在机制。 与创伤应激相关的功能性脑异常。具体来说，我们将探讨 对创伤性应激引起的急性威胁（“恐惧”：RDoC 领域）持续敏感背后的机制 在成年早期。髓鞘化很可能是为了提高传导速度而进化的，但在灰质 (GM) 中， 它减少轴突萌芽、突触密度和神经可塑性。最近令人兴奋的发现表明 皮质和皮质下灰质中的髓磷脂发育具有高度可塑性，并受到新物质的强烈影响。 经验和学习，即使在成年生活中也是如此。重要的是，髓磷脂形成少突胶质细胞对 环境压力源，因此可能提供一种新的机制，通过该机制异常的结构和 大脑发生功能变化。 我们实验室的人脑成像数据表明，患有一系列继发于创伤后应激障碍（PTSD）症状的受试者 成人创伤暴露会增加海马 (HP)、额叶和颞叶 GM 中的髓磷脂含量。 重要的是，髓磷脂含量比潜在的混杂变量更能预测症状的严重程度。 此外，我们发现啮齿动物的成年创伤应激暴露会导致 少突胶质细胞 (OG) 和齿状回 (DG)（GM 结构）中的髓磷脂含量。与人类相似 我们的初步数据显示，大鼠的症状严重程度（恐惧评分）与 DG 显着相关 OG 和髓磷脂含量。总的来说，这些发现提供了一个转化模型，可以更好地理解 人类少突胶质细胞和髓磷脂可塑性的机制。在这个提案中，我们将测试假设 成年期间的创伤性压力暴露会导致皮质和皮质下 GM 的髓鞘形成增加 在对恐惧记忆至关重要的区域。具体来说，我们预计只有在以下情况下才会看到髓鞘形成的增加： 随后对压力暴露后的严重威胁变得敏感。此外，我们假设 髓鞘形成增加将限制主要内在功能连接（IFC）的正常运作 网络。这种动物与人类的综合设计实现了创新的多层次和因果探索。 此外，我们还关注成人大脑中髓磷脂可塑性作为创伤诱发的介质的新作用。 急性威胁症状。 目标 1 关注海马灰质髓鞘形成是否预测创伤后的问题 对严重威胁的敏感性。目标 2 的重点是创伤暴露是否会影响 皮质和皮质下 GM 髓鞘形成预测网络连接和恐惧记忆。