Early life stress (ELS) is a risk factor in the development of psychiatric disorders. The underlying biological mechanisms governing this phenomenon are not fully understood, but dysregulation of stress responses is likely to play a key role. Males and females differ in their propensity to develop psychiatric disorders, with far higher rates of anxiety, major depressive disorder, affective disorders and post-traumatic stress disorder found in women. We hypothesized that sex differences in response to ELS may play a crucial role in differential vulnerability between the sexes. To test this, we evaluated the consequences of pre-pubertal stress (PPS) on the HPA axis in adult female and male Lister Hooded rats. PPS animals were exposed to swim, restraint and elevated platform stress on postnatal days 25-27, controls remained in their home cage. Once adult, animals were either a) sacrificed directly and brains collected or b) sacrificed 20 minutes or 1 week after a social test and trunk blood collected. In the female hippocampal formation, PPS increased expression of FKBP5 and AVPR1a. In the female prefrontal cortex, PPS resulted in increased glucocorticoid receptor expression, increased glucocorticoid:mineralocorticoid (GR:MR) receptor expression ratio and decreased AVPR1a expression. Females exposed to PPS did not show the normal rise in blood corticosterone levels following a social interaction test. In contrast, PPS did not alter the expression of oxytocin or oxytocin receptors, and no effects of PPS were seen in males. However, striking sex differences were found. Females had higher oxytocin receptor expression in the prefrontal cortex and AVPR1a and oxytocin expression in the hypothalamus, whereas males demonstrated higher expression of GR, MR, GR:MR, FKBP5 and oxytocin receptor in the hypothalamus. These results demonstrate heightened reactivity of the female HPA axis to PPS and may help explain why in humans females display an increased susceptibility to certain stress-related psychopathologies.LAY SUMMARYWomen are at greater risk of developing several psychiatric illnesses. Using a rodent model, we show that the female stress system is more reactive to the lasting effects of early life stress. This heightened reactivity of the female stress response may help explain why women are at a greater risk of developing psychiatric disorders.

中文翻译：

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女性HPA轴显示出对青春期前压力的敏感性增强。

早期生活压力（ELS）是精神疾病发展的危险因素。尚未完全了解控制这种现象的潜在生物学机制，但是应激反应的失调可能起关键作用。男性和女性发展精神病的倾向不同，女性的焦虑症，重度抑郁症，情感障碍和创伤后应激障碍的发生率要高得多。我们假设响应ELS的性别差异可能在性别差异脆弱性中起关键作用。为了测试这一点，我们评估了成年雌性和雄性利斯特连帽大鼠在HPA轴上的青春期前压力（PPS）的后果。在产后25-27天，PPS动物暴露于游泳，约束和平台压力升高的情况下，对照组仍留在自己的笼子里。成年后，对动物进行a）直接处死并收集大脑，或b）在进行社交测试后20分钟或1周处死并收集躯干血液。在女性海马结构中，PPS增加了FKBP5和AVPR1a的表达。在女性前额叶皮层中，PPS导致糖皮质激素受体表达增加，糖皮质激素：矿物质皮质激素（GR：MR）受体表达比率增加和AVPR1a表达降低。社交互动测试后，暴露于PPS的女性未显示血液中皮质类固醇激素水平正常升高。相反，PPS不会改变催产素或催产素受体的表达，并且在男性中未见PPS的作用。但是，发现了惊人的性别差异。雌性在前额皮层中的催产素受体表达较高，下丘脑中的AVPR1a和催产素的表达较高，而雄性在下丘脑中的GR，MR，GR：MR，FKBP5和催产素受体的表达较高。这些结果表明，女性HPA轴对PPS的反应性增强，并且可能有助于解释为什么女性在人类中表现出对某些与压力相关的精神病学易感性增强的原因。妇女在患多种精神病的风险更大。使用啮齿动物模型，我们表明女性压力系统对生命早期压力的持久影响更具反应性。女性压力反应的这种增强的反应性可以帮助解释为什么女性处于患精神病的更大风险中。下丘脑中的FKBP5和催产素受体。这些结果表明，女性HPA轴对PPS的反应性增强，并且可能有助于解释为什么女性在人类中表现出对某些与压力相关的精神病学易感性增强的原因。妇女在患多种精神病的风险更大。使用啮齿动物模型，我们表明女性压力系统对生命早期压力的持久影响更具反应性。女性压力反应的这种增强的反应性可以帮助解释为什么女性处于患精神病的更大风险中。下丘脑中的FKBP5和催产素受体。这些结果表明，女性HPA轴对PPS的反应性增强，并且可能有助于解释为什么女性在人类中表现出对某些与压力相关的精神病学易感性增强的原因。妇女在患多种精神病的风险更大。使用啮齿动物模型，我们表明女性压力系统对生命早期压力的持久影响更具反应性。女性压力反应的这种增强的反应性可以帮助解释为什么女性处于患精神病的更大风险中。发明内容妇女更有可能患多种精神病。使用啮齿动物模型，我们表明女性压力系统对生命早期压力的持久影响更具反应性。女性压力反应的这种增强的反应性可以帮助解释为什么女性处于患精神病的更大风险中。发明内容妇女更有可能患多种精神病。使用啮齿动物模型，我们表明女性压力系统对生命早期压力的持久影响更具反应性。女性压力反应的这种增强的反应性可以帮助解释为什么女性处于患精神病的更大风险中。