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: 10091987
• 负责人: E SHERWOOD BROWN
• 金额: $ 74.48万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091987
• 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 (Brain); Hormones; Human; Hydrocortisone; Impairment; Interdisciplinary Study; Literature; Magnetic Resonance Imaging; Major Depressive Disorder; 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; base; cognitive system; dentate gyrus; depressive symptoms; early life adversity; experience; hippocampal atrophy; hippocampal subregions; hypothalamic-pituitary-adrenal axis; men; multimodality; neurocognitive test; neurogenesis; neuroimaging; pre-clinical; response; sex

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.

抽象的 慢性皮质类固醇（CS）暴露与记忆和海马的变化有关 人类和动物模型。海马有高浓度的糖皮质激素受体 （GCR），临床前文献表明，在CA3区域的顶端树突缩短 CS给药后，海马和齿状回（DG）的神经发生降低。在人类中 压力和CS暴露都与声明性记忆性能的下降有关（一个过程 由海马介导）。据报道，声明性记忆和海马萎缩的损害在 由于库欣氏病而导致CS过度释放的患者，以及我们的小组在接受的患者中 处方CS治疗。这些发现对情绪障碍患者具有重要意义 大抑郁症患者（MDD）的大部分集显示了HPA轴激活的证据，升高 皮质醇，重要的是，对CSS对HPA轴和声明性记忆的影响。 因此，对皮质类固醇的耐药性似乎是MDD的结果。 我们先前的工作显示了接受处方CSS（例如泼尼松）或 健康的对照短暂施用了氢化可的松（皮质醇）。我们的飞行员数据表明​​3天管理 氢化可的松的声明性记忆可逆下降，与任务相关的减少 海马激活，以及显着但可逆的海马体积减少。减少 女性海马体积较大，与血清皮质醇水平的增加相关。基于 这些数据，我们建议检查声明性记忆的变化，并使用最先进的高位 分辨率多模式神经影像学，包括结构和功能（即基于任务和静止状态）MRI， 在男性和女人的健康对照中，作为探索性的目标，一个沮丧的群体给定了3天 暴露于氢化可的松（160 mg/天）或安慰剂。该研究将把临床前发现转化为人类 提供有关皮质醇反应的可能性别差异的宝贵数据，并首次确定 对急性CS效应最敏感的人类的特定海马子场（例如CA3/DG）。使用 静止状态fMRI数据和整个大脑连接使用图理论方法，我们将确定 皮质醇暴露对功能性脑网络的影响。此外，这将是第一次使用的研究 神经影像学以比较大脑对抑郁症患者与控制的人对CSS的反应，并确定 抑郁症患者是否在海马内表现出糖皮质激素的抗性。我们假设 在CA3/DG子场中，海马对急性CSS的反应最大，女性比在 与对照组相比，男人和沮丧的人会对CSS表现出钝性的海马反应。一个 多学科研究团队在CS对大脑和海马子领域具有丰富经验 神经影像学和先前的研究合作历史将进行该项目。