Neurobiological mechanisms of perceived stress and their modification through behavioral intervention

项目摘要 应激的主观感受介导急性和慢性应激源对长期心理健康的影响 结果，因此代表了诸如创伤后应激障碍和抑郁症等疾病的重要风险因素。拟议 该项目将通过识别感知压力的新的假定大脑机制来填补知识空白，从而允许 更好地识别高危人群，并为寻求 来增强抗压能力该职业发展奖将为候选人提供以下方面的培训 先进的结构和弥散加权MRI方法以及基础知识的教学和指导培训 临床试验研究。这种新的训练将被用来测试关于海马神经元的新假设。 贡献感知压力，并通过正念干预修改这些机制。中 研究1从社区中选取了300名个体作为样本，探讨了感知压力与 和模式分离行为，这是一个依赖于星座的过程，允许细粒度的歧视 安全与威胁的背景下，并已在理论上与过度概括的恐惧和 负面影响使用海马的高分辨率结构成像和多图谱分割， 1将研究模式分离行为，海马子场体积， 对日常生活压力源和急性实验室压力源的感知。在Aim 2中，高级弥散加权成像 方法将被用来深入了解海马神经突的密度和方向（轴突和 树突）。这将允许一个新的调查的微观结构相关的主观感知 压力，假设包括海马内神经突密度降低和海马神经元的一致性取向降低。 连接海马体和内侧前额叶皮质的白色物质束。在研究2中，将有80名参与者 随机分配到一个等待名单控制组或正念减压（MBSR），这是已知的减少 压力的主观感受。目标3将测试MBSR参与者是否表现出模式的改善 分离行为、海马体积和海马微结构，以及这些海马 变化与预期的感知压力减少有关。新的培训将促进目标1-2 在海马的高级结构成像和高级扩散加权成像方法中， 由在这些领域具有广泛专业知识的培训团队提供支持，并通过丰富的资源实现 一个世界级的脑成像中心目标3将得到以下方面的教学、体验和指导培训的支持： 通过NIH资助的临床和转化研究所进行临床研究的基础 （卢旺达问题国际法庭）。总的来说，该项目的研究和培训目标旨在阐明新的神经生物学 感知压力的机制，并提供先进的神经成像方法和临床试验的新培训 方法论该奖项将使候选人能够进行未来的干预研究，旨在预防 通过这些神经生物学靶点来控制压力相关疾病的发展。

PROJECT SUMMARY Subjective perceptions of stress mediate the effects of acute and chronic stressors on long-term psychological outcomes, and thus represent an important risk factor for disorders such as PTSD and depression. The proposed project will fill a knowledge gap by identifying novel putative brain mechanisms of perceived stress, thus allowing for better identification of at-risk individuals and the development of treatment targets for interventions that seek to enhance stress resilience. This Career Development Award will provide the candidate with training in advanced structural and diffusion-weighted MRI methods and didactic and mentored training in the fundamentals of clinical trials research. This new training will be leveraged to test novel hypotheses regarding hippocampal contributions to perceived stress, and modification of these mechanisms by a mindfulness intervention. In a sample of 300 individuals from the community, Study 1 will investigate relationships between perceived stress and pattern separation behavior, a hippocampal-dependent process that allows for fine-grained discrimination of safe vs. threatening contexts, and which has been theoretically linked to over-generalization of fear and negative affect. Using high-resolution structural imaging and multi-atlas segmentation of the hippocampus, Aim 1 will investigate relationships between pattern separation behavior, hippocampal subfield volumes, and perceptions of daily life stressors and acute laboratory stressors. In Aim 2, advanced diffusion-weighted imaging methods will be used to gain insight into the density and orientation of hippocampal neurites (axons and dendrites). This will allow for a novel investigation of the microstructural correlates of subjectively perceived stress, hypothesized to include reduced neurite density within the hippocampus and less coherent orientation of white matter tracts linking the hippocampus and medial prefrontal cortex. In Study 2, 80 participants will be randomized to a wait-list control group or mindfulness-based stress reduction (MBSR), which is known to reduce subjective perceptions of stress. Aim 3 will test whether MBSR participants demonstrate improvements in pattern separation behavior, hippocampal volume, and hippocampal microstructure, and whether these hippocampal changes are associated with expected reductions in perceived stress. Aims 1-2 will be facilitated by new training in advanced structural imaging of the hippocampus and advanced diffusion-weighted imaging methods, supported by a training team with extensive expertise in these domains and made possible by the rich resources of a world-class brain imaging center. Aim 3 will be supported by didactic, experiential, and mentored training in the fundamentals of clinical research through the NIH-funded Institute for Clinical and Translational Research (ICTR). Collectively, the research and training aims of this project seek to illuminate novel neurobiological mechanisms of perceived stress and provide new training in advanced neuroimaging methods and clinical trials methodology. This award will enable the candidate to conduct future intervention studies aimed at preventing the development of stress-related disorders by engaging these neurobiological targets.