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: 10333336
• 负责人: E SHERWOOD BROWN
• 金额: $ 73.6万
• 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/10333336
• 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; multimodal neuroimaging; 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）暴露与记忆和海马体的变化有关 人类和动物模型中。海马体有高浓度的糖皮质激素受体 （GCR），临床前文献表明 CA3 区域的顶端树突缩短 CS 给药后，海马体和齿状回 (DG) 神经发生减少。在人类中， 压力和 CS 暴露都与陈述性记忆性能（一个过程）的下降有关。 由海马体介导）。据报道，陈述性记忆受损和海马萎缩 因库欣病而导致 CS 释放过多的患者，以及我们小组接受治疗的患者 处方CS治疗。这些发现对情绪障碍患者具有重要意义 大部分患有重度抑郁症 (MDD) 的人表现出 HPA 轴激活的证据 皮质醇，更重要的是，抵抗 CS 对 HPA 轴和陈述性记忆的影响。 因此，对皮质类固醇的抵抗似乎是 MDD 的结果。 我们之前的研究表明，接受处方 CS（例如泼尼松）或 健康对照组短暂服用氢化可的松（皮质醇）。我们的试点数据表明 3 天的给药 氢化可的松与陈述性记忆的可逆性下降、任务相关性的下降有关 海马体激活，海马体体积显着但可逆地减少。减少 女性的海马体积更大，并且与血清皮质醇水平的增加相关。基于 根据这些数据，我们建议检查陈述性记忆的变化，以及使用最先进的高科技 分辨率多模式神经影像，包括结构和功能（即基于任务和静息状态）MRI， 在男性和女性健康对照组中，以及作为探索性目标的抑郁组中，给予 3 天的治疗 暴露于氢化可的松（160 毫克/天）或安慰剂。该研究将把临床前研究结果转化为人类， 提供有关皮质醇反应中可能存在的性别差异的宝贵数据，并首次确定 人类特定的海马亚区（例如 CA3/DG）对急性 CS 效应最敏感。使用 使用图论方法静息态功能磁共振成像数据和全脑连接组学，我们将确定 皮质醇暴露对功能性大脑网络的影响。此外，这将是第一个使用 通过神经影像学比较抑郁症患者与对照组大脑对 CS 的反应，并确定 抑郁症患者的海马体内是否表现出糖皮质激素抵抗。我们假设 海马对急性 CS 的反应在 CA3/DG 亚区最强，女性比女性更强 男性，并且与对照组相比，抑郁症患者的海马体对 CS 的反应会减弱。一个 多学科研究团队在 CS 对大脑和海马亚区的影响方面拥有丰富的经验 神经影像学以及之前的研究合作历史将负责该项目。