Sex differences in pain-induced modulation of corticotropin-releasing hormone neurons in the dorsolateral part of the stria terminalis in mice
Sex differences in pain-induced modulation of corticotropin-releasing hormone neurons in the dorsolateral part of the stria terminalis in mice
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DOI：
10.1016/j.brainres.2021.147688
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发表时间：
2021-10-15
期刊：
影响因子：
2.9
通讯作者：
Funabashi, Toshiya
中科院分区：
文献类型：
--
作者：
Hagiwara, Hiroko;Sakimura, Kenji;Funabashi, Toshiya
我们之前报道了雌性偏向性的、性别特异性的终纹背外侧床核（dl BST）参与大鼠福尔马林诱导的疼痛反应。本研究探讨了疼痛对小鼠行为的影响。由于dl - BST密集分布着促肾上腺皮质激素释放激素（CRH）神经元，我们在一个CRH基因启动子（促肾上腺皮质激素释放因子[CRF]-Venus Delta Neo）控制修饰黄色荧光蛋白（Venus）表达的小鼠系中，研究了雄性和雌性小鼠dl - BST CRH神经元这些参数的性别差异。在dl BST中，大约92%的金星阳性细胞同时也是CRH mrna阳性，与性别无关。因此，利用金星荧光鉴定的细胞被认为是CRH神经元。在注射福尔马林后5-15分钟，野生型小鼠的疼痛诱导行为在间期（注射福尔马林后5-15分钟）存在雌性偏向性差异，但在后期（第2期，15-60分钟）没有这种差异。在CRF-Venus Delta Neo小鼠中，在早期（第1期，0-5分钟）或间期观察到雌性偏向性差异，但在第2期没有。利用注射福尔马林后获得的CRF-Venus Delta Neo小鼠急性BST切片进行膜片钳记录，显示出微型兴奋性突触后电流（mEPSCs）和微型抑制性突触后电流（mIPSCs）。值得注意的是，在注射了福尔马林的雌性小鼠中，表达venus的细胞中mEPSCs的频率高于给药的雌性小鼠。注射福尔马林后，雄性小鼠mEPSC频率未见增加。注射福尔马林对两性mEPSC和mIPSC振幅均无影响。疼痛引起的CRH神经元mEPSC频率变化是相依赖性的。结果表明，BST CRH神经元的兴奋性突触输入在时间上随着疼痛反应的行为性别差异而增强，表明疼痛信号以性别依赖的方式改变BST CRH神经元的兴奋性。
We earlier reported female-biased, sex-specific involvement of the dorsolateral bed nucleus of the stria terminalis (dl BST) in the formalin-induced pain response in rats. The present study investigated pain effects on mice behaviors. Because the dl BST is densely populated with corticotropin-releasing hormone (CRH) neurons, we examined sex differences in these parameters for the dl BST CRH neurons in male and female mice of a mouse line for which the CRH gene promoter (corticotropin-releasing factor [CRF]-Venus Delta Neo) controls the expression of the modified yellow fluorescent protein (Venus).Approximately 92% of Venus-positive cells in the dl BST were also CRH mRNA-positive, irrespective of sex. Therefore, the cells identified using Venus fluorescence were regarded as CRH neurons. A female-biased sex difference was observed in pain-induced behaviors during the interphase (5-15 min after formalin injection) but not during the later phase (phase 2, 15-60 min) in wild-type mice. In CRF-Venus Delta Neo mice, a female-biased difference was observed in either the earlier phase (phase 1, 0-5 min) or the interphase, but not in phase 2. Patch-clamp recordings taken using an acute BST slice obtained from a CRF-Venus Delta Neo mouse after formalin injection showed miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). Remarkably, the mEPSCs frequency was higher in the Venus-expressing cells of formalininjected female mice than in vehicle-treated female mice. Male mice showed no increase in mEPSC frequency by formalin injection. Formalin injection had no effect on mEPSC or mIPSC amplitudes in either sex. Pain induced changes in mEPSC frequency in putative CRH neurons were phase-dependent. Results show that excitatory synaptic inputs to BST CRH neurons are temporally enhanced along with behavioral sex differences in pain response, suggesting that pain signals alter the BST CRH neurons excitability in a sex-dependent manner.