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: 10516079
• 负责人: Daniela KAUFER
• 金额: $ 66.43万
• 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 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516079
• 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; Human; Image; Insula of Reil; Learning; Life; Measures; Mediator; 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.

项目总结/摘要 这项研究将探讨适应不良的髓鞘形成作为一个潜在的机制， 与创伤压力有关的大脑功能异常。具体来说，我们将探讨 对创伤性压力引起的急性威胁（“恐惧”：RDoC域）持续敏感性背后的机制 在成年早期。髓鞘形成很可能是为了提高传导速度，但在灰质（GM）中， 它减少轴突发芽、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鞘发育具有高度可塑性， 经验和学习，即使在成年生活中。重要的是，髓鞘形成少突胶质细胞对 环境应激源，因此可能提供一种新的机制，通过这种机制， 大脑的功能发生了变化。 我们实验室的人脑成像数据显示，患有一系列继发于创伤后应激障碍症状的受试者， 成人创伤暴露增加了海马（HP）、额叶和颞叶GM中的髓鞘含量。 重要的是，髓鞘含量预测症状严重程度超过潜在的混杂变量。 此外，我们发现啮齿类动物的成年创伤应激暴露会增加 少突胶质细胞（OG）和齿状回（DG）（GM结构）中的髓鞘含量。类似于人类 受试者，我们的初步数据显示，大鼠的症状严重程度（恐惧评分）与DG显著相关 OG和髓鞘含量。总的来说，这些发现提供了一个翻译模型，以更好地理解 人类少突胶质细胞和髓鞘可塑性的机制。在本提案中，我们将检验假设 成年期的创伤应激暴露导致皮质和皮质下GM髓鞘形成增加， 在恐惧记忆的关键区域。具体地说，我们希望只在那些 随后在压力暴露后变得对急性威胁敏感。此外，我们假设， 髓鞘形成的增加将限制主要内在功能连接（IFC）的正常功能 网络.这种动物-人类的综合设计使创新的多层次和因果关系的探索成为可能。 此外，我们还关注了髓鞘可塑性在成人脑中的一个新作用，它是创伤诱导的脑损伤的一种介质。 急性威胁症状 目的1：探讨海马灰质髓鞘化是否预示创伤后海马神经元损伤 对严重威胁的敏感性。目标2关注的问题是，创伤暴露对 皮质和皮质下GM髓鞘形成预测网络连接和恐惧记忆。

项目成果

Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair.

• DOI: 10.3390/biom11020290
• 发表时间: 2021-02-16
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Breton JM;Long KLP;Barraza MK;Perloff OS;Kaufer D
• 通讯作者: Kaufer D

Juvenile exposure to acute traumatic stress leads to long-lasting alterations in grey matter myelination in adult female but not male rats.

• DOI: 10.1016/j.ynstr.2021.100319
• 发表时间: 2021-05
• 期刊: Neurobiology of stress
• 影响因子: 5
• 作者: Breton JM;Barraza M;Hu KY;Frias SJ;Long KLP;Kaufer D
• 通讯作者: Kaufer D

Impulsivity as a multifactorial construct and its relationship to PTSD severity and threat sensitivity.

冲动是一种多因素构造及其与PTSD严重性和威胁敏感性的关系。

• DOI: 10.1016/j.psychres.2020.113468
• 发表时间: 2020-11
• 期刊: Psychiatry research
• 影响因子: 11.3
• 作者: Young DA;Neylan TC;Zhang H;O'Donovan A;Inslicht SS
• 通讯作者: Inslicht SS

Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans.

• DOI: 10.1038/s41398-021-01745-5
• 发表时间: 2021-12-13
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Long KLP;Chao LL;Kazama Y;An A;Hu KY;Peretz L;Muller DCY;Roan VD;Misra R;Toth CE;Breton JM;Casazza W;Mostafavi S;Huber BR;Woodward SH;Neylan TC;Kaufer D
• 通讯作者: Kaufer D

Ventromedial and insular cortical volume moderates the relationship between BDNF Val66Met and threat sensitivity.

• DOI: 10.1016/j.jpsychires.2021.08.012
• 发表时间: 2021-10
• 期刊: Journal of psychiatric research
• 影响因子: 4.8
• 作者: Young DA;Chao LL;Zhang H;Metzler T;Ross J;Richards A;O'Donovan A;Inslicht SS;Neylan TC
• 通讯作者: Neylan TC