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.
项目概要/摘要
该提案将检查适应不良灰质(GM)髓鞘形成作为支撑的候选机制
创伤后应激障碍 (PTSD) 中已明确的两种功能性脑异常:
威胁响应网络的连通性(TRN:定义为海马体(HIP)、杏仁核(AMYG)、
前岛叶 (INS) 和背侧前扣带皮层 (dACC)),以及默认模式网络的破坏
(DMN)。在许多大脑区域中都观察到依赖于经验和活动的 GM 髓鞘形成
与精神疾病有广泛的相关性。虽然依赖经验的髓鞘形成加速了
神经传导,GM 中的髓鞘形成已被证明可降低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,TRN 中过度的 GM 髓鞘化会导致 PTSD
在超连接显着网络(SN;包括 AMYG、dACC 和 INS,但不包括 HIP)中。请参阅“桥接
框架”部分)和连接不良且活性低下的 DMN。考虑到髓磷脂的发育和重新
皮质和皮质下 GM 中的髓鞘形成均对治疗药物有反应,证实了我们的模型
可能会产生治疗创伤后应激障碍(PTSD)的新靶点,这种疾病对药物治疗有抵抗力
干涉。我们提出的模型产生了支持“突触断开”的候选机制
Krystal 及其同事提出的综合症来解释 PTSD 中功能性大脑连接受损的情况。这是
同样值得注意的是,最近的证据表明 PTSD 患者的 DMN 断开与
大额叶白质轨迹的破坏。因此,关键结构中过度的 GM 髓鞘化可能会提供
对这一现象的解释。在 PTSD 病例中结合使用尸检神经病理学与
脑库对照,以及匹配病例对照设计中 3T 的体内神经影像学,我们将检查 PTSD 是否
与 TRN 结构中髓磷脂含量增加以及突触和神经突密度减少有关。
最后,我们将测试 TRN 中 GM 髓磷脂的增加和神经突密度的减少是否是静息状态增加的原因
SN 内的状态 (RS) 连接性和 DMN 内的 RS 连接性降低
科目。由国家 PTSD 脑库提供的死后神经病理学与体内神经病理学的整合
神经影像学将使对 GM 髓鞘形成及其相关性的高度新颖但可广泛测试的探索成为可能
PTSD 改变了人脑的后果。
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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