Investigating Fear System Myelination in PTSD Using In Vivo and Post Mortem Data

使用体内和死后数据研究 PTSD 中的恐惧系统髓鞘形成

• 批准号: 10635220
• 负责人: BERTRAND R HUBER
• 金额: $ 70.44万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635220
• 关键词: Acceleration; Affect; Amygdaloid structure; Animal Model; Anterior; Autopsy; Axon; Brain; Brain imaging; Brain region; Caliber; Data; Development; Dorsal; Exhibits; Fright; Hippocampus; Human; Image; Insula of Reil; Intervention; Mental disorders; Methods; Modeling; Myelin; Myelin Sheath; Neural Conduction; Neurites; Neuronal Plasticity; Post-Traumatic Stress Disorders; Rest; Structure; Study Subject; Synapses; Syndrome; System; Testing; Therapeutic Agents; Thick; Water; brain abnormalities; brain tissue; case control; cingulate cortex; density; design; experience; functional disability; gray matter; in vivo; myelination; neuroimaging; neuropathology; novel; remyelination; response; white matter

PROJECT SUMMARY/ABSTRACT This proposal will examine maladaptive gray matter (GM) myelination as a candidate mechanism underpinning two functional brain abnormalities well established in Posttraumatic Stress Disorder (PTSD): hyper- connectedness of the threat response network (TRN: defined as hippocampus (HIP), amygdala (AMYG), anterior insula (INS), and dorsal anterior cingulate cortex (dACC)), and disruption of the default mode network (DMN). Experience- and activity-dependent GM myelination have been observed in many brain regions and have broad relevance to psychiatric disorders. While experience-dependent myelination evolved to accelerate nerve conduction, myelination in GM has been shown to reduce synaptic density and synapse-based neuroplasticity in animal models. Our model proposes that excess GM myelination in the TRN in PTSD results in a hyperconnected salience network (SN; which includes AMYG, dACC, and INS but not HIP. See “Bridging Frameworks” section) and a poorly connected and hypoactive DMN. Given that myelin development and re- myelination in both cortical and subcortical GM are responsive to therapeutic agents, confirming our model could lead to novel targets for treatment of PTSD, a condition that has resisted pharmacotherapeutic intervention. Our proposed model yields a candidate mechanism underpinning the “synaptic disconnection” syndrome proposed by Krystal and colleagues to explain impaired functional brain connectivity in PTSD. It is also noteworthy that recent evidence suggests that DMN dysconnectivity in PTSD is not associated with the disruption of large frontal white matter tracks. As such, excess GM myelination in key structures may supply an explanation for this phenomenon. Using a combination of postmortem neuropathology in PTSD cases versus brain bank controls, and in vivo neuroimaging at 3T in a matched case control design, we will examine if PTSD is associated with increased myelin content and decreased synaptic and neurite density in the TRN structures. Finally, we will test if increased GM myelin and decreased neurite density in TRN account for increased resting state (RS) connectivity within the SN and decreased RS connectivity within the DMN in the same living subjects. Integration of postmortem neuropathology, afforded by the National PTSD Brain Bank, and in vivo neuroimaging will enable a highly novel but broadly testable exploration of GM myelination and its consequences in the human brain as modified by PTSD.

项目摘要/摘要 该提案将检查适应不良的灰质（GM）髓鞘形成作为候选机制的基础 在创伤后应激障碍（PTSD）中良好确定的两个功能性脑异常： 威胁响应网络的连接性（TRN：定义为海马（HIP），Amygdala（Amyg）， 前岛（INS）和背扣带回皮层（DACC）以及默认模式网络的破坏 （DMN）。在许多大脑区域都观察到了经验和活动依赖性的转基因髓鞘形成 与精神疾病具有广泛的相关性。而依赖经验的髓鞘形成了加速 神经传导，GM中的髓鞘化已显示可降低突触密度和基于突触 动物模型中的神经可塑性。我们的模型提案超过了PTSD结果中TRN中GM髓鞘的建议 在超连接的显着性网络中 框架”部分）和连接性较差的DMN。 皮质和皮质下GM中的髓鞘化对治疗剂有反应，证实了我们的模型 可能导致新的PTSD治疗靶标，这种疾病已经抵抗了药物治疗 干涉。我们提出的模型产生了一种基于“突触断开”的候选机制 克里斯塔尔和同事提出的综合征解释了PTSD中功能性脑连通性受损。这是 同样值得注意的是，最近的证据表明，PTSD中的DMN功能障碍与 大型额叶白质轨道的破坏。因此，在关键结构中超过GM髓鞘化可能会提供 解释这一现象。在PTSD病例中使用后神经病理学的组合与 在匹配的案例控制设计中，脑库控制和体内神经影像学处于3T，我们将检查PTSD是否存在 与TRN结构中的髓磷脂含量增加以及突触和神经元密度降低有关。 最后，我们将测试GM髓磷脂增加并降低TRN的神经蛋白密度，以增加静止 在SN内的状态（RS）连接，并在同一生活中提高了DMN内的RS连接性 主题。国家PTSD脑库提供的后验尸神经病理学的整合，体内 神经影像学将使对GM髓鞘形成及其的高度新颖但可以广泛测试 PTSD修饰的人脑的后果。