Toth Mate, Flandreau Elizabeth I, Deslauriers Jessica, Geyer Mark A, Mansuy Isabelle M, Merlo Pich Emilio, Risbrough Victoria B
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA.
Neuropsychopharmacology. 2016 May;41(6):1681-90. doi: 10.1038/npp.2015.338. Epub 2015 Nov 5.
Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.
尽管早期生活应激是包括创伤后应激障碍（PTSD）在内的焦虑症发展的重要风险因素，但其潜在机制尚不清楚。促肾上腺皮质激素释放激素（CRH）在PTSD患者和经历早期生活应激的个体中存在紊乱，因此可能介导早期生活应激对PTSD风险的影响。我们假设在早期发育过程中前脑CRH信号过度增强足以增加成年期对创伤的反应。为了验证这一假设，我们在双突变小鼠（Camk2a-rtta2×tetO-Crh）的早期生活（青春期前，CRHOEdev）期间诱导了短暂的、前脑特异性的CRH过表达，并测试了它们成年后对PTSD捕食者应激模型的行为和基因表达反应。在一组暴露和未暴露于CRHOEdev的小鼠中，在暴露于捕食者应激7-15天后检查回避和觉醒行为。在另一组中，在捕食者应激7天后检查暴露和未暴露于CRHOEdev的小鼠前脑Crhr1、Crhr2和Fkbp51的基因表达变化。CRHOEdev在雄性和雌性小鼠中均独立于捕食者应激诱导惊吓反应性显著增加和惊吓抑制降低。捕食者应激后的回避行为高度依赖于性别和CRHOEdev暴露。应激雌性表现出强烈的回避反应，且不受CRHOEdev影响，而雄性仅在同时暴露于CRHOEdev和应激时才出现显著回避。定量实时PCR分析表明，未暴露于CRHOEdev的雄性小鼠杏仁核和终纹床核中Crhr2表达在应激后有显著变化，而暴露于CRHOEdev的雄性小鼠则没有。与暴露于CRHOEdev的雄性小鼠类似，雌性小鼠在应激后Crhr2基因表达也没有显著变化。应激和CRHOEdev暴露也显著降低了雄性小鼠皮质Fkbp51的表达，但对雌性小鼠没有影响。这些发现表明，早期生活中前脑CRH信号过度增强足以增加成年创伤的持久影响，并减弱雄性小鼠对应激的Crhr2表达变化。这些数据支持了越来越多关于创伤反应存在显著性别差异的证据，并支持将CRHR2作为PTSD风险候选机制进行进一步研究。
