Examining the intersection of sex and stress in modelling neuropsychiatric disorders.
Examining the intersection of sex and stress in modelling neuropsychiatric disorders.
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DOI：
10.1111/j.1365-2826.2009.01843.x
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发表时间：
2009-03
影响因子：
3.2
通讯作者：
Bale TL
中科院分区：
文献类型：
--
作者：
Goel N;Bale TL
有性别偏见的神经精神障碍，包括严重抑郁症和精神分裂症，是发达国家残疾的主要原因。压力敏感性升高已被认为是疾病发作的关键潜在因素。应激敏感性的性别差异与CRF和5-羟色胺神经传递有关，它们是情绪和应对反应的重要中枢调节因子。为了阐明应激相关疾病易感性的神经生物学基础，建立适当的应激通路失调动物模型至关重要。此外，在这些模型中，在应激反应行为、生理学和中枢应激途径成熟方面的性别差异比较是必不可少的。我们实验室和其他人最近的研究已经开始调查压力和性别的交叉点，其中通过产前压力经历或早期生活操作的压力途径失调的小鼠模型的发展提供了对发育脆弱性点的洞察。此外，检查这些途径的成熟，包括功能的重要性，组织和激活的影响，性腺激素对压力反应是必不可少的，以确定何时压力敏感性的性别差异可能开始。在这样的研究中，我们已经发现了明显的性别差异，在压力应对策略的激活效应的睾酮产生的女性，显示男性样的策略在测试中的被动应对，但类似于女性在测试中的主动应对。在应激敏感性升高的第二个模型中，在妊娠早期经历产前应激的雄性小鼠表现出雌性化的生理和行为应激反应，并且对低剂量的SSRI高度敏感。对表达和表观遗传模式的分析揭示了这些小鼠CRF和糖皮质激素受体基因的变化。从机制上讲，怀孕早期的压力对胎盘基因表达产生了显著的性别依赖性影响，支持改变胎儿运输关键生长因子和营养物质。这些小鼠模型检查的变化和激素对压力途径的发展的影响提供了必要的洞察力，如何特定的压力反应可以在发展的早期重新编程，导致压力敏感性和神经精神疾病的脆弱性的性别差异。
Sex-biased neuropsychiatric disorders, including major depressive disorder and schizophrenia, are the major cause of disability in the developed world. Elevated stress sensitivity has been proposed as a key underlying factor in disease onset. Sex differences in stress sensitivity are associated with CRF and serotonin neurotransmission, important central regulators of mood and coping responses. To elucidate the underlying neurobiology of stress-related disease predisposition, it is critical to develop appropriate animal models of stress pathway dysregulation. Further, the inclusion of sex difference comparisons in stress responsive behaviors, physiology, and central stress pathway maturation in these models is essential. Recent studies by our lab and others have begun to investigate the intersection of stress and sex where the development of mouse models of stress pathway dysregulation via prenatal stress experience or early life manipulations has provided insight into points of developmental vulnerability. In addition, examination of the maturation of these pathways including the functional importance of the organizational and activational effects of gonadal hormones on stress responsivity is essential for determination of when sex differences in stress sensitivity may begin. In such studies, we have detected distinct sex differences in stress coping strategies where activational effects of testosterone produced females that displayed male-like strategies in tests of passive coping, but were similar to females in tests of active coping. In a second model of elevated stress sensitivity, male mice experiencing prenatal stress early in gestation showed feminized physiological and behavioral stress responses, and were highly sensitive to a low dose of SSRI. Analyses of expression and epigenetic patterns revealed changes in CRF and glucocorticoid receptor genes in these mice. Mechanistically, stress early in pregnancy produced a significant sex-dependent effect on placental gene expression supportive of altered fetal transport of key growth factors and nutrients. These mouse models examining alterations and hormonal effects on development of stress pathways provide necessary insight into how specific stress responses can be reprogrammed early in development resulting in sex differences in stress sensitivity and neuropsychiatric disease vulnerability.
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影响因子：
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