Astrocyte Activation in Locus Coeruleus Is Involved in Neuropathic Pain Exacerbation Mediated by Maternal Separation and Social Isolation Stress.
Astrocyte Activation in Locus Coeruleus Is Involved in Neuropathic Pain Exacerbation Mediated by Maternal Separation and Social Isolation Stress.
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DOI：
10.3389/fphar.2017.00401
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发表时间：
2017
影响因子：
5.6
通讯作者：
Tokuyama S
中科院分区：
文献类型：
--
作者：
Nakamoto K;Aizawa F;Kinoshita M;Koyama Y;Tokuyama S
我们先前的研究表明，与早期生活应激相关的情绪障碍会加剧神经损伤所致的机械性异位痛觉。在几项焦虑测试中观察到了性别差异，但在机械性痛觉异常中没有观察到性别差异。为了阐明这些发现背后的机制，我们现在调查了星形胶质细胞在母亲分离和社会隔离(MSSI)作为早期生活应激(MSSI)的小鼠中参与情绪障碍和增强神经损伤诱导的机械性痛觉异常的作用。免疫组织化学方法检测星形胶质细胞标志物--胶质纤维酸性蛋白(GFAP)在各脑区的表达。在MSSI后，雌性小鼠蓝斑(LC)中GFAP的表达显著增加，而雄性小鼠则无明显变化，与7周龄和12周龄时的行为变化相一致。将经脂多糖(LPS)处理的星形胶质细胞培养上清液注射到包括LC在内的局部脑区。LC内注射培养的星形胶质细胞条件培养液，可增加雄性和雌性小鼠的GFAP表达、焦虑样行为和机械性痛觉异常。此外，焦虑样行为的增加与机械性异位痛觉的增加相关。这些发现表明，暴露于MSSI后，情绪障碍和神经损伤导致的机械性痛觉异常至少部分是通过LC中星形胶质细胞的激活来调节的。雄性而不是雌性小鼠在生长过程中可能对MSSI应激表现出抵抗力。
Our previous studies demonstrated that emotional dysfunction associated with early life stress exacerbated nerve injury-induced mechanical allodynia. Sex differences were observed in several anxiety tests, but not in mechanical allodynia. To elucidate the mechanism underlying these findings, we have now investigated the involvement of astrocytes in emotional dysfunction and enhancement of nerve injury-induced mechanical allodynia in mice subjected to maternal separation combined with social isolation (MSSI) as an early life stress. We measured expression of glial fibrillary acidic protein (GFAP), an astrocyte maker, in each brain area by immunohistochemistry. GFAP expression in the locus coeruleus (LC) of female, but not of male mice, significantly increased after MSSI, corresponding to the behavioral changes at 7 and 12 weeks of age. Lipopolysaccharide (LPS)-treated astrocyte-derived supernatant was administered to local brain regions, including LC. Intra-LC injection of conditioned medium from cultured astrocytes treated with LPS increased GFAP expression, anxiety-like behavior and mechanical allodynia in both male and female mice. Furthermore, increases in anxiety-like behavior correlated with increased mechanical allodynia. These findings demonstrate that emotional dysfunction and enhanced nerve injury-induced mechanical allodynia after exposure to MSSI are mediated, at least in part, by astrocyte activation in the LC. Male but not female mice may show resistance to MSSI stress during growth.