Brewer Judson A, Bethin Kathleen E, Schaefer Michele L, Muglia Lisa M, Vogt Sherri K, Weninger Stacie C, Majzoub Joseph A, Muglia Louis J
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Stress. 2003 Jun;6(2):121-5. doi: 10.1080/1025389031000116460.
To define the molecular pathways modulating adrenal and behavioral responses to stress, we have generated mice with inactivation of hypothalamic neuropeptides and signaling pathways. Studies in mice deficient in corticotropin-releasing hormone (CRH) have revealed the essential role for CRH in adrenal glucocorticoid production in response to many physiological and psychological stressors. Immune system activation in CRH-deficient mice provides a unique exception to the necessity for CRH in stimulating adrenal glucocorticoid production. By analyzing mice deficient in interleukin-6 (IL-6) and CRH, we find that restoration of glucocorticoid output with inflammation is largely mediated by dysregulated IL-6 production. Current studies focus on identifying cellular and gene targets by which glucocorticoids regulate immune system function. In contrast to impaired adrenocortical responses to stress, CRH-deficient mice exhibit normal behavioral responses to stress. To determine signaling pathways that may contribute to the behavioral responses to stress, we have generated and analyzed mice deficient in adenylyl cyclase type 8 (AC8). AC8 deficient mice have intact adrenocortical responses to stress, but an inability to undergo stress-induced alterations in behavior.
为了确定调节肾上腺和对应激反应的行为反应的分子途径，我们培育了下丘脑神经肽和信号通路失活的小鼠。对促肾上腺皮质激素释放激素（CRH）缺乏的小鼠的研究揭示了CRH在应对许多生理和心理应激源时肾上腺糖皮质激素产生中的重要作用。CRH缺乏小鼠的免疫系统激活是CRH刺激肾上腺糖皮质激素产生必要性的一个独特例外。通过分析白细胞介素-6（IL-6）和CRH缺乏的小鼠，我们发现炎症时糖皮质激素输出的恢复很大程度上是由失调的IL-6产生介导的。目前的研究集中在确定糖皮质激素调节免疫系统功能的细胞和基因靶点。与肾上腺皮质对应激的反应受损相反，CRH缺乏的小鼠对应激表现出正常的行为反应。为了确定可能导致对应激行为反应的信号通路，我们培育并分析了腺苷酸环化酶8（AC8）缺乏的小鼠。AC8缺乏的小鼠对压力有完整的肾上腺皮质反应，但无法经历压力诱导的行为改变。
