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Corticosterone Metabolism Locally Regulates Glucocorticoid Exposure in Brain

皮质酮代谢局部调节大脑中糖皮质激素的暴露

基本信息

批准号：
9197339
负责人：
Michelle Rensel
金额：
$ 7.7万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-17 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197339
关键词：
Adrenal Glands Adult Behavior Biochemical Blood Brain Brain region Bromodeoxyuridine Buffers Carbenoxolone Cell Proliferation Chronic Cognition Corticosterone Development Enzymes Exposure to Female Future Glucocorticoids Hippocampus (Brain)Homeostasis Hormones Human Hydroxysteroid Dehydrogenases Hypothalamic structure In Vitro Label Lateral Measures Mediating Mediator of activation protein Messenger RNA Metabolism Microdialysis Modeling Molecular NADH dehydrogenase (ubiquinone)Nature Neurodegenerative Disorders Neuronal Plasticity Neurosecretory Systems Oxidoreductase Pattern Peripheral Pharmacology Physiology Play Regulation Reporting Research Rodent Rodent Model Role Sex Characteristics Slice Songbirds Specificity Stress Testing Ventricular Vertebrates Work acute stress attenuation brain tissue cognitive function enzyme activity experimental study human disease hypothalamic-pituitary-adrenal axis in vitro Assay in vivo inhibitor/antagonist male neural circuit neurogenesis neuron loss novel public health relevance receptor regional difference relating to nervous system response sex zebra finch

项目摘要

DESCRIPTION (provided by applicant): Glucocorticoids (CORT) are essential mediators of physiology, behavior, and cognition. CORT receptors are expressed in the vertebrate brain and play a key role in mediating these responses; however, local control over CORT levels is necessary because over-exposure can be detrimental, leading to neuronal death and inhibition of neurogenesis (Mirescu and Gould, 2006; Sapolsky et al., 1985). One way the brain may achieve this control is through the actions of CORT-metabolizing enzymes 11β hydroxysteroid dehydrogenase types 1 (11β HSD1) and 2 (11β HSD2), which re-activate and de-activate CORT, respectively. While the adult rodent brain appears to abundantly express 11β HSD1 but not 11β HSD2 (Holmes et al., 2006), the songbird brain expresses type 2 and previous research has shown that this expression may be responsible for producing a regional difference in brain CORT and a buffering of the brain from the effects of stress (Katz et al., 2010; Rensel et al., 2014). In addition, it is unclear whether the rodent model is an accurate representation of the neuroendocrine system governing CORT exposure in humans; therefore there is a need for alternative models. The proposed research has two specific aims: first, the research will test the hypothesis that the CORT-metabolizing enzymes 11β HSD1 and 11β HSD2 act in concert to dynamically regulate CORT levels in discrete brain regions and limit fluctuations in blood from reaching the brain. Experiments will assess the regional distribution of both enzymes in the songbird brain, then utilize in vitro assays to establish enzyme activity and specificity in response to CORT. In addition, in vivo microdialysis and retrodialysis of an 11β HSD inhibitor will be employed in the hippocampus to assess the functional effects of 11β HSD type 2 as a buffer against CORT elevation coming from the periphery. Previous research found that neurogenesis in the songbird lateral ventricular zone (VZ) is reduced by CORT in males but not females, suggesting greater CORT inactivation in females that may be neuroprotective (Katz et al., 2008). The second specific aim of this research will test the hypothesis that the 11β HSDs are responsible for this sex difference. Sections of brain containing the lateral VZ will be exposed to CORT with or without an 11β HSD inhibitor and BrdU labeling will be quantified. Thus, experiments conducted at multiple levels of organization (both in vitro and in vivo) as well as measures of mRNA, enzyme activity, and direct neural measures of CORT will establish the nature of the mechanisms controlling local CORT exposure in brain. This research has the potential to uncover novel mechanisms of CORT regulation and inform development of future treatments for human disease characterized by glucocorticoid excess and dysregulation.

描述（由申请人提供）：糖皮质激素（CORT）是生理、行为和认知的基本介质。CORT受体在脊椎动物脑中表达，并在介导这些反应中起关键作用;然而，对CORT水平的局部控制是必要的，因为过度暴露可能是有害的，导致神经元死亡和神经发生的抑制（Mirescu和Gould，2006; Sapolsky等人，1985年）。大脑可以实现这种控制的一种方式是通过CORT代谢酶11β羟基类固醇脱氢酶1型（11β HSD 1）和2型（11β HSD 2）的作用，它们分别重新激活和去激活CORT。虽然成年啮齿动物脑似乎大量表达11β HSD 1，但不表达11β HSD 2（Holmes et al.，2006），鸣禽大脑表达2型，并且先前的研究已经表明，这种表达可能负责产生大脑CORT的区域差异和大脑对压力影响的缓冲（Katz等人，2010; Rensel等人，2014年）。此外，目前还不清楚啮齿动物模型是否是控制人类CORT暴露的神经内分泌系统的准确代表;因此需要替代模型。这项研究有两个具体的目标：首先，该研究将测试以下假设：CORT代谢酶11β HSD 1和11β HSD 2协同作用，动态调节离散大脑区域的CORT水平，并限制血液到达大脑的波动。实验将评估这两种酶在鸣禽脑中的区域分布，然后利用体外测定来建立酶活性和对CORT的特异性反应。此外，将在海马中采用11β HSD抑制剂的体内微透析和后透析，以评估11β HSD 2型作为缓冲剂对抗来自外周的CORT升高的功能效应。先前的研究发现，鸣禽侧脑室区（VZ）中的神经发生在雄性中而不是雌性中被CORT减少，这表明雌性中更大的CORT失活可能是神经保护性的（Katz等人，2008年）。本研究的第二个具体目的是检验11β HSDs与这种性别差异有关的假设。将含有外侧VZ的脑切片暴露于含或不含11β HSD抑制剂的CORT，并定量BrdU标记。因此，在多个组织水平（体外和体内）进行的实验以及mRNA的测量，酶活性和CORT的直接神经测量将建立控制大脑中局部CORT暴露的机制的性质。这项研究有可能揭示CORT调节的新机制，并为未来以糖皮质激素过量和失调为特征的人类疾病的治疗提供信息。