Identifying early Behavioral and molecular markers of future stress sensitivity
Identifying early Behavioral and molecular markers of future stress sensitivity
复制标题
DOI：
10.1210/en.2007-0479
复制
发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Bale, Tracy L.
中科院分区：
文献类型：
--
作者：
Goel, Nirupa;Bale, Tracy L.
青春期是神经发育的可塑期，此时应激途径发生关键成熟。异常成熟可能预示着未来的压力敏感性和情感障碍风险。为了确定压力相关疾病易感性的潜在早期标志物，我们使用应激敏感性升高、CRF 受体 2 (CRFR2) 缺陷小鼠的遗传模型，检查了雄性青春期小鼠与成年小鼠的生理和行为应激反应。两种基因型的幼年小鼠均表现出比成年小鼠更高的基础皮质酮水平和应激诱导的皮质酮水平，表明下丘脑-垂体-肾上腺轴的总体敏感性在成年期降低。然而，缺乏 CRFR2 的幼年小鼠表现出该基因型成年小鼠典型的延迟应激恢复，这表明应激敏感性的早期标志。这些敏感小鼠的海马糖皮质激素受体表达减少的成年表型也在青春期期间被检测到。这种减少可能是下丘脑-垂体-肾上腺轴负反馈受损的原因，因此是压力敏感表型的早期指标。对压力行为反应的检查表明，CRFR2 缺陷的小鼠表现出过度的青春期后成熟。尽管野生型小鼠在青春期后并未改变其对引发压力的大理石的埋藏反应，但 CRFR2 缺陷小鼠的埋藏行为却显着增加。我们的结论是，异常青春期应激途径成熟的识别可能预示着成人应激敏感性的升高和未来对应激相关情感障碍的易感性。
Puberty is a plastic period of neurological development when critical maturation of stress pathways occurs. Abnormal maturation may be predictive of future stress sensitivity and affective disorder risk. To identify potential early markers of stress-related disease predisposition, we examined physiological and behavioral stress responses in male pubertal mice compared with adults, using a genetic model of elevated stress sensitivity, CRF receptor-2 (CRFR2)-deficient mice. Juvenile mice of both genotypes exhibited greater basal and stress-induced corticosterone levels than adult mice, indicating that overall hypothalamic-pituitary-adrenal axis sensitivity diminishes in adulthood. However, juvenile CRFR2-deficient mice displayed a delayed stress recovery typical of adults of this genotype, suggesting an early marker of stress sensitivity. The adult phenotype of reduced hippocampal glucocorticoid receptor expression in these sensitive mice was also detected during puberty. This reduction may account for an impaired hypothalamic-pituitary-adrenal axis negative feedback and as such be an early indicator of a stress-sensitive phenotype. Examination of behavioral responses to stress revealed that CRFR2-deficient mice show exaggerated postpubertal maturation. Although wild-type mice did not alter their burying response to stress-provoking marbles after puberty, CRFR2-deficient mice showed a dramatic increase in burying behavior. We conclude that identification of abnormal pubertal stress pathway maturation may be predictive of adult heightened stress sensitivity and future susceptibility to stress-related affective disorders.