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条件性敲除大鼠脑内糖皮质激素受体导致恐惧和应对行为出现性别特异性缺陷。

Conditional deletion of glucocorticoid receptors in rat brain results in sex-specific deficits in fear and coping behaviors.

机构信息

Department Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, United States.

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.

出版信息

Elife. 2019 Jul 22;8:e44672. doi: 10.7554/eLife.44672.

DOI:10.7554/eLife.44672
PMID:31329100
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6645713/
Abstract

Glucocorticoid receptors (GR) have diverse functions relevant to maintenance of homeostasis and adaptation to environmental challenges. Understanding the importance of tissue-specific GR function in physiology and behavior has been hampered by near-ubiquitous localization in brain and body. Here we use CRISPR/Cas9 gene editing to create a conditional knockdown in Sprague Dawley rats. To test the impact of cell- and region-specific knockdown on physiology and behavior, we targeted knockdown to output neurons of the prelimbic cortex. Prelimbic knockdown of in females caused deficits in acquisition and extinction of fear memory during auditory fear conditioning, whereas males exhibited enhanced active-coping behavior during forced swim. Our data support the utility of this conditional knockdown rat to afford high-precision knockdown of across a variety of contexts, ranging from neuronal depletion to circuit-wide manipulations, leveraging the behavioral tractability and enhanced brain size of the rat as a model organism.

摘要

糖皮质激素受体 (GR) 具有多种与维持内稳态和适应环境挑战相关的功能。理解组织特异性 GR 功能在生理和行为中的重要性，受到了脑和全身近乎普遍存在的定位的阻碍。在这里，我们使用 CRISPR/Cas9 基因编辑技术在 Sprague Dawley 大鼠中创建了一种条件性敲低。为了测试细胞和区域特异性敲低对生理和行为的影响，我们将敲低靶向到额前皮质的输出神经元。在雌性大鼠中，前额皮质的 GR 敲低导致在听觉恐惧条件反射中恐惧记忆的获得和消退缺陷，而雄性大鼠在强迫游泳中表现出增强的主动应对行为。我们的数据支持这种条件性敲低大鼠的实用性，它可以在各种情况下提供高精确度的 GR 敲低，范围从神经元耗竭到全回路操作，利用大鼠作为模型生物的行为可操作性和增强的大脑大小。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/19e7a1a9c99a/elife-44672-app1-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/983079aad669/elife-44672-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/59a7c9341af7/elife-44672-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/afd8b1ab6d9a/elife-44672-app1-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/ca514d546de7/elife-44672-app1-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/898cd13cc72c/elife-44672-app1-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/19e7a1a9c99a/elife-44672-app1-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/983079aad669/elife-44672-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/968b2ba2b9a9/elife-44672-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/a04e32d5ae7c/elife-44672-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/59a7c9341af7/elife-44672-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/afd8b1ab6d9a/elife-44672-app1-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/ca514d546de7/elife-44672-app1-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/898cd13cc72c/elife-44672-app1-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d11/6645713/19e7a1a9c99a/elife-44672-app1-fig4.jpg

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