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

项目摘要/摘要 这项建议将研究适应不良的灰质髓鞘形成作为支持的候选机制。 在创伤后应激障碍(PTSD)中确立的两种功能性脑异常：高- 威胁反应网络的连通性(TRN：定义为海马体(HIP)、杏仁核(AMYG)、 前脑岛(INS)和背侧前扣带回(DACC)，以及默认模式网络的中断 (DMN)。经验和活动依赖的GM髓鞘形成在许多大脑区域和 与精神障碍有着广泛的相关性。而依赖经验的髓鞘形成进化为加速 神经传导，GM中的髓鞘形成已被证明降低突触密度和以突触为基础 动物模型中的神经可塑性。我们的模型认为创伤后应激障碍患者TRN中过度的GM髓鞘形成 在超连接的显著网络(SN；包括AMYG、dACC和INS，但不包括HIP。请参阅“桥接” 框架“部分)，以及连接不畅和不活跃的DMN。鉴于髓鞘的发育和再- 皮质和皮质下GM的髓鞘形成对治疗药物有反应，证实了我们的模型 可能导致治疗PTSD的新靶点，PTSD是一种抵抗药物治疗的疾病 干预。我们提出的模型提出了一种支持“突触断开”的候选机制 克里斯特尔和他的同事们提出了一种综合症，用来解释创伤后应激障碍的脑功能连接性受损。它是 同样值得注意的是，最近的证据表明，创伤后应激障碍患者的DMN连接障碍与 额叶大脑白质径迹中断。因此，关键结构中过量的GM髓鞘形成可能会提供 对这一现象的解释。在创伤后应激障碍病例中使用死后神经病理学组合与 在匹配的病例对照设计中，我们将检查创伤后应激障碍 与TRN结构中髓鞘含量增加、突触和轴突密度减少有关。 最后，我们将测试TRN内GM髓鞘增加和轴突密度降低是否与静息时间增加有关。 SN内的状态(RS)连通性和同一生活中DMN内的RS连通性降低 研究对象。由国家创伤后应激障碍脑库提供的死后神经病理学与体内的整合 神经成像将使一种高度新颖但可广泛测试的转基因髓鞘形成及其 创伤后应激障碍对人类大脑的影响。

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.