Region-specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats
Region-specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats
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DOI：
10.1002/glia.23476
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发表时间：
2019-01-01
期刊：
影响因子：
6.2
通讯作者：
Gomes, Catarina A.
中科院分区：
文献类型：
--
作者：
Duarte, Joana Mendes;Gaspar, Rita;Gomes, Catarina A.
流行病学研究提供了令人信服的证据表明，产前压力，通过过度的母亲糖皮质激素暴露，与精神疾病在以后的生活。我们最近报道，与产前暴露于地塞米松（DEX，一种合成糖皮质激素）相关的焦虑与内侧前额叶皮层（mPFC）中小胶质细胞的性别特异性重塑相关，mPFC是焦虑相关疾病的核心脑区。小胶质细胞形态的性别差异，女性焦虑的患病率较高以及焦虑对认知的负面影响，使我们专门评估了产前暴露于地塞米松（子宫内DEX，iuDEX）的雌性大鼠的认知行为和相关回路（即mPFC-背海马，dHIP）以及小胶质细胞形态。我们报告说，iuDEX损害识别记忆和恶化mPFC和dHIP之间的神经元同步。这些功能缺陷被dHIP中的小胶质细胞超分支和mPFC中的分支减少所掩盖，显示出在出生后和成年期不同脑区域中的小胶质细胞形态的异质性重塑，其不同地影响情绪和认知。腺苷A（2A）受体（A（2A）R）是小胶质细胞形态和生理学的核心调节因子，其慢性阻断可改善认知缺陷，但不能改善焦虑样行为。值得注意的是，A（2A）R阻断纠正了dHIP中的小胶质细胞形态和mPFC-dHIP同步化的缺乏，进一步预示了它们在认知功能中的作用。
Epidemiologic studies have provided compelling evidence that prenatal stress, through excessive maternal glucocorticoids exposure, is associated with psychiatric disorders later in life. We have recently reported that anxiety associated with prenatal exposure to dexamethasone (DEX, a synthetic glucocorticoid) correlates with a gender-specific remodeling of microglia in the medial prefrontal cortex (mPFC), a core brain region in anxiety-related disorders. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behavior and associated circuits (namely mPFC-dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (in utero DEX, iuDEX). We report that iuDEX impaired recognition memory and deteriorated neuronal synchronization between mPFC and dHIP. These functional deficits are paralleled by microglia hyper-ramification in the dHIP and decreased ramification in the mPFC, showing a heterogeneous remodeling of microglia morphology, both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A(2A) receptors (A(2A)R), which are core regulators of microglia morphology and physiology, ameliorated the cognitive deficits, but not the anxiety-like behavior. Notably, A(2A)R blockade rectified both microglia morphology in the dHIP and the lack of mPFC-dHIP synchronization, further heralding their role in cognitive function.