A multimodal investigation of positive and negative modulators of the medial temporal hippocampal system

项目总结/摘要 美国正在与种族主义作斗争，这是一场持续的公共卫生危机。突出的社会环境 种族主义是美国黑人生活中的慢性压力源，与消极的精神和身体健康有关 结果。内侧颞海马（MTH）系统的完整性是可以通过外部经验改变的， 这些因素也可能增加其脆弱性。该系统的相反调节剂包括心肺 健身和慢性压力，这是差异与模式分离，神经计算亲， cess依赖于海马体，海马体在记忆编码过程中对消除高度相似的刺激至关重要。 我们的实验室已经表明，增加心肺健康积极影响MTH系统在年轻和 老年人相反，社会环境慢性应激的动物模型和人类神经成像研究 显示了该系统的广泛结构和功能重组。海马长轴也 显示了情感（前）和认知（后）的分化，这表明神经基质在 情绪障碍和慢性压力。有证据表明，MTH的神经认知缺陷在年轻的成年人 与急性应激和情绪障碍有关，但这还没有被调查为慢性应激的后果。 应力种族主义的负面影响可能解释了不同年龄组的情绪障碍在严重性和慢性化方面的差异。 美国黑人在目标1中，我们证明了1）更大的心肺适应性预测MTH增加 年轻人而非老年人的皮质厚度和2）更大的感知辨别力预测MTH降低 在不同年龄组的老年人中。在目标2中，我们假设更大的种族主义将与 MTH神经认知缺陷的黑人年轻人。技术培训将侧重于获得以下方面的专门知识： 基于任务的高分辨率fMRI和行为和fMRI数据的高级多元统计建模。 因此，关于更大的感知种族主义，我们试图从行为上研究与空间和非空间的关联。 空间模式分离性能。接下来，我们将进行先进的多元统计建模， 验证更大的种族主义是否会调节与NIMH研究领域标准相关的fMRI活动 海马功能的相关性，记忆相似性任务。最后，在目标3中，我们建议确定一个职位， 博士生导师，在情绪障碍，慢性压力和/或神经炎症方面具有专业知识，可以训练我 使用正电子发射断层扫描等方式进行实验设计和数据分析， 神经炎症，由于其与压力源的良好联系。广泛的，长期的目标是建立大脑健康 公平研究能力，确定交叉边际造成的长期压力的可改变或缓解因素， 化的身份最后，该提案旨在解决BRAIN倡议的科学审查和高优先级问题。 使用多模态方法研究人类大脑与行为和认知的关系的研究领域 积极的结果，回答了NIMH最近的呼吁，调查社会环境压力源和减轻 因素，以及美国国立卫生研究院推动调查健康的社会决定因素如何影响健康生活。

PROJECT SUMMARY/ABSTRACT The United States is grappling with racism as an ongoing public health crisis. A salient socioenvironmental chronic stressor in the lives of Black Americans, racism is associated with negative mental and physical health outcomes. The integrity of the medial temporal hippocampal (MTH) system is modifiable by extrinsic experiential factors, which can also increase its vulnerability. Opposite modulators of this system include cardiorespiratory fitness and chronic stress, which are differentially associated with pattern separation, a neurocomputational pro- cess reliant on the hippocampus that is vital for disambiguating highly similar stimuli during memory encoding. Our lab has shown that increased cardiorespiratory fitness positively impacts the MTH system in both young and older adults. In contrast, animal models and human neuroimaging studies of socioenvironmental chronic stress have shown extensive structural and functional reorganization of this system. The hippocampal long-axis also shows affective (anterior) and cognitive (posterior) differentiation, suggesting a neural substrate perturbed in mood disorders and by chronic stress. There is evidence of MTH neurocognitive deficits in young adulthood related to acute stress and mood disorders, but this has not been investigated as a consequence of chronic stress. The negative impact of racism may explain disparities in the severity and chronicity of mood disorders in Black Americans. In Aim 1, we demonstrate that 1) greater cardiorespiratory fitness predicts increased MTH cortical thickness in young but not older adults and 2) greater perceived discrimination predicts reduced MTH volume in a diverse group of older adults. In Aim 2 we hypothesize that greater perceived racism will be associ- ated with MTH neurocognitive deficits in Black young adults. Technical training will focus on gaining expertise in task-based high-resolution fMRI and advanced multivariate statistical modeling of behavioral and fMRI data. Thus, in relation to greater perceived racism, we seek to behaviorally examine associations with spatial and non- spatial pattern separation performance. Next, we will conduct advanced multivariate statistical modeling to quan- tify whether greater perceived racism modulates fMRI activity associated with a NIMH Research Domain Criteria correlate of hippocampal function, the Mnemonic Similarity Task. Finally, in Aim 3 we propose to identify a post- doctoral mentor with expertise in mood disorders, chronic stress, and/or neuroinflammation who can train me in experimental design and data analysis using modalities such as Positron Emission Tomography to investigate neuroinflammation, due to its well-established link to stressors.The broad, long term goal is to build brain health equity research capacity, identifying modifiable or mitigating factors of chronic stress due to intersecting margin- alized identities. Finally, this proposal seeks to address the BRAIN Initiative’s Scientific Review and High Priority Research Area for using multimodal methods to investigate the human brain in relation to behavioral and cogni- tive outcomes, answers a recent call by the NIMH to investigate socioenvironmental stressors and mitigating factors, and a push by the NIH to investigate how social determinants of health impact healthy living.