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
基本信息
- 批准号:10635220
- 负责人:
- 金额:$ 70.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccelerationAffectAmygdaloid structureAnimal ModelAnteriorAutopsyAxonBrainBrain imagingBrain regionCaliberDataDevelopmentDorsalExhibitsFrightHippocampusHumanImageInsula of ReilInterventionMental disordersMethodsModelingMyelinMyelin SheathNeural ConductionNeuritesNeuronal PlasticityPost-Traumatic Stress DisordersRestStructureStudy SubjectSynapsesSyndromeSystemTestingTherapeutic AgentsThickWaterbrain abnormalitiesbrain tissuecase controlcingulate cortexdensitydesignexperiencefunctional disabilitygray matterin vivomyelinationneuroimagingneuropathologynovelremyelinationresponsewhite matter
项目摘要
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.
项目总结/摘要
这项建议将研究适应不良的灰质(GM)髓鞘形成作为一个候选机制,
在创伤后应激障碍(PTSD)中,有两种功能性大脑异常:
威胁反应网络(TRN:定义为海马体(HIP),杏仁核(AMYG),
前扣带皮层(INS)和背侧前扣带皮层(dACC)),以及默认模式网络的破坏
(DMN)。经验和活动依赖性GM髓鞘形成已在许多脑区观察到,
与精神疾病有着广泛的关联当经验依赖性髓鞘形成进化到加速
在神经传导中,GM中的髓鞘形成已经显示出减少突触密度和基于突触的
动物模型中的神经可塑性。我们的模型提出,PTSD患者TRN中GM髓鞘形成过多,
在超连接显著性网络(SN)中,其包括AMYG、dACC和INS,但不包括HIP。参见“桥接
框架”部分)和一个连接不良和低活性的DMN。考虑到髓磷脂的发育和再-
皮层和皮层下GM的髓鞘形成对治疗药物有反应,证实了我们的模型
可能为治疗创伤后应激障碍提供新的靶点,创伤后应激障碍是一种药物治疗无效的疾病,
干预我们提出的模型产生了一个支持“突触断开”的候选机制。
Krystal及其同事提出的PTSD综合征来解释PTSD中受损的功能性大脑连接。是
同样值得注意的是,最近的证据表明,PTSD中的DMN连接障碍与
大的额叶白色物质轨迹的破坏。因此,关键结构中的GM髓鞘形成过多可能会提供
解释这一现象。结合创伤后应激障碍病例的死后神经病理学和
脑库对照,以及在匹配的病例对照设计中的3 T活体神经成像,我们将检查PTSD是否
与髓磷脂含量增加和TRN结构中突触和神经突密度降低有关。
最后,我们将测试是否GM髓鞘增加和TRN神经突密度降低导致静息状态下的神经元数量增加,
SN内的RS连接性和DMN内的RS连接性降低
科目整合死后神经病理学,由国家创伤后应激障碍脑库提供,
神经影像学将使一个高度新颖但广泛可测试的探索GM髓鞘形成及其
创伤后应激障碍对人脑的影响
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('BERTRAND R HUBER', 18)}}的其他基金
VA Biorepository: Gulf War Veterans' Illnesses Biorepository
VA 生物储存库:海湾战争退伍军人疾病生物储存库
- 批准号:
10515289 - 财政年份:2014
- 资助金额:
$ 70.44万 - 项目类别:
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