Exploring the Effects of Corticosteroids on the Human Hippocampus using Neurocognitive Testing and High-Resolution Brain Imaging

使用神经认知测试和高分辨率脑成像探索皮质类固醇对人类海马的影响

• 批准号: 10556437
• 负责人: E SHERWOOD BROWN
• 金额: $ 72.79万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556437
• 关键词: Acute; Adrenal Cortex Hormones; Age; Animal Model; Animals; Apical; Asthma; Atrophic; Behavior; Brain; Brain imaging; Brain region; Cells; Chronic; Clinical; Collaborations; Control Groups; DSM-V; Data; Dendrites; Depressed mood; Dexamethasone; Diagnosis; Exposure to; Feedback; Functional Imaging; Functional Magnetic Resonance Imaging; Glucocorticoid Receptor; Glucocorticoids; Grant; Graph; Hippocampus; Hormones; Human; Hydrocortisone; Impairment; Interdisciplinary Study; Literature; Magnetic Resonance Imaging; Major Depressive Disorder; Maps; Measures; Mediating; Memory; Memory impairment; Mental Depression; Mood Disorders; National Institute of Mental Health; Outcome; Patients; Perception; Performance; Persons; Physical activity; Pituitary Corticotropin Secreting Tumor; Pituitary-dependent Cushing' s disease; Placebos; Population; Prednisone; Process; Recording of previous events; Reporting; Research; Research Domain Criteria; Resistance; Resolution; Rest; Rheumatism; Serum; Severities; Sex Differences; Sleep; Stress; Structure; Testing; Time; Translating; Visuospatial; Woman; Work; cognitive system; comparison control; dentate gyrus; depressive symptoms; early life adversity; experience; hippocampal atrophy; hippocampal subregions; hypothalamic-pituitary-adrenal axis; men; multimodal neuroimaging; neurocognitive test; neurogenesis; neuroimaging; pre-clinical; response; sex; structural imaging

Abstract Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus in both humans and in animal models. The hippocampus has a high concentration of glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are associated with a decline in declarative memory performance (a process mediated by the hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in patients with excessive CS release due to Cushing's disease, and, by our group, in patients receiving prescription CS therapy. These findings have important implications for patients with mood disorders, as a large subset of people with major depressive disorder (MDD) show evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to corticosteroids appears to be a consequence of MDD. Our prior work has shown memory deficits in persons receiving prescription CSs (e.g., prednisone) or healthy controls briefly administered hydrocortisone (cortisol). Our pilot data suggest that 3-day administration of hydrocortisone is associated with reversible decline in declarative memory, decrease in task-related hippocampal activation, and a significant, but reversible, decrease in hippocampal volume. Decrease in hippocampal volume was greater in women and correlated with increases in serum cortisol levels. Based on these data, we propose to examine changes in declarative memory, as well as use state-of-the-art high- resolution multimodal neuroimaging, including structural and functional (i.e., task-based and resting state) MRI, in both men and women healthy controls, and, as an exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or placebo. The study will translate preclinical findings to humans, provide valuable data on possible sex differences in the response to cortisol and, for the first time, identify specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS effects. Using resting state fMRI data and whole brain connectomics using graph theoretical approaches, we will determine the effects of cortisol exposure on functional brain networks. Furthermore, this will be the first study to use neuroimaging to compare the brain's response to CSs in people with depression vs. controls, and determine whether depressed people demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men, and that depressed people will show a blunted hippocampal response to CSs compared to controls. A multidisciplinary research team with extensive experience in CS effects on the brain and hippocampal subfield neuroimaging, and a prior history of research collaboration, will conduct the project.

摘要 慢性皮质类固醇(CS)暴露与记忆和海马体的变化有关 在人类和动物模型中都是如此。海马体中有高浓度的糖皮质激素受体 (GCRs)，临床前文献显示在CA3区的顶端树突缩短。 海马区和齿状回(DG)神经发生减少。在人类身上， 压力和CS暴露都与陈述性记忆成绩下降有关(这是一个过程 由海马体调节)。陈述性记忆障碍和海马区萎缩的报告发表在 由于库欣病导致CS释放过多的患者，我们组的患者接受了 处方CS疗法。这些发现对情绪障碍患者具有重要的意义，因为 一大群患有严重抑郁障碍(MDD)的人显示HPA轴激活，升高 皮质醇，更重要的是，在HPA轴和陈述性记忆中抵抗CSS的影响。 因此，对皮质类固醇的耐药性似乎是MDD的结果。 我们先前的工作表明，接受处方css(例如，泼尼松)或 健康对照组短暂使用氢化可的松(皮质醇)。我们的试点数据显示，3天的服药时间 氢化可的松的浓度与陈述性记忆、任务相关记忆的可逆性下降有关 海马体激活，显著但可逆的海马体体积减少。减少 女性的海马体体积更大，并与血清皮质醇水平的升高相关。基于 这些数据，我们建议检查声明性记忆的变化，以及使用最先进的高级 分辨率多模式神经成像，包括结构和功能(即，基于任务和静息状态)MRI， 男性和女性均为健康对照组，作为探索性目标，抑郁症组给予3天 接触氢化可的松(160毫克/天)或安慰剂。这项研究将把临床前的发现转化为人类， 提供有关皮质醇反应中可能存在的性别差异的有价值的数据，并首次确定 人类对急性CS效应最敏感的特定海马亚区(例如，CA3/DG)。vbl.使用 静息状态的fMRI数据和全脑连接图使用图论方法，我们将确定 皮质醇暴露对脑功能网络的影响。此外，这将是第一次使用 神经成像，比较抑郁症患者和对照组的大脑对CSS的反应，并确定 抑郁症患者是否在海马区表现出糖皮质激素抵抗。我们假设 在CA3/DG亚区，海马体对急性CS的反应最大，女性比女性更强 与对照组相比，抑郁症患者的海马区对css的反应迟钝。一个 在CS对大脑和海马亚区的影响方面拥有丰富经验的多学科研究团队 神经成像和以前的研究合作历史将进行该项目。