Stressor Controllability and Neuroendocrine Systems

描述(申请人提供)：本资助申请中的实验建议使用动物模型来描述应激期间神经内分泌系统的调节。人们希望，这些研究的结果将开始阐明为什么这些系统在人类抑郁症中变得失调。抑郁症患者的下丘脑-垂体-肾上腺轴(HPA)和下丘脑-垂体-甲状腺轴(HPT)均有改变。这些神经内分泌系统的活动和调节将在成年雄性大鼠身上使用被认为是抑郁症的动物模型的范例来表征。该范式是可控/不可控(C/NC)应激范式。在这种模式下，一种动物，即执行动物，可以结束他的压力(温和的脚电刺激)，但他的带轭的伴侣不能。这两个应激组受到相同的身体压力，但在应对的心理方面有所不同。像抑郁症患者一样，带轭的动物表现出逃避地塞米松(DEX)对HPA轴的抑制作用。此外，我们实验室最近的工作也表明，有轭的动物，而不是执行动物，降低了甲状腺激素水平；甲状腺激素水平的降低也与人类抑郁有关。在拟议的实验中，将测量下丘脑中神经肽mRNA和hnRNA的水平，以表征在C/NC应激过程中和之后对HPA和HPT轴的中枢驱动。这些神经肽mRNA和hnRNA水平也将在经地塞米松预处理的执行动物和带轭动物中进行测定。DEX穿透大脑并激活糖皮质激素受体的能力也将在执行动物和受轭动物身上确定。这些研究的结果将充分描述执行动物和带轭动物的HPA和HPT轴的活动，并有助于阐明逃避DEX抑制的机制。反复暴露在C/NC压力下的影响也将被确定。基础和应激诱导的激素水平变化将在应激7天或14天后进行测量。神经肽mRNA水平的变化也将被测定，以及编码糖皮质激素、盐皮质激素和甲状腺激素受体的mRNA的测量。这些研究的结果应该提供有关重要的神经内分泌系统的信息，这些系统经常在人类抑郁症中变得失调。

DESCRIPTION (provided by applicant): The experiments in this grant application propose to use animal models to describe the regulation of neuroendocrine systems during stress. It is hoped that the results of these studies will begin to elucidate why these systems become dysregulated in human depression. Changes in both the hypothalamic-pituitaryadrenal axis (HPA) and the hypothalamic-pituitary-thyroid axis (HPT) have been documented in depressed patients. The activity and regulation of these neuroendocrine systems will be characterized in adult male rats using a paradigm that has been considered an animal model of depression. The paradigm is the controllable/non-controllable (C/NC) stress paradigm. In this paradigm one animal, the executive animal, can terminate his stress (a mild-electric foot shock), but his yoked partner cannot. Both stress groups receive an identical physical stressor, but differ in the psychological aspect of coping. The yoked animals exhibit escape from the suppressive effects of dexamethasone (DEX) on the HPA axis, as do depressed patients. Furthermore, recent work from our lab has also demonstrated that yoked animals, but not executive, have decreased levels of thyroid hormone levels; decreased in thyroid hormone levels have also been linked to human depression. In the proposed experiments, neuropeptide mRNA and hnRNA levels will be measured in the hypothalamus to characterize central drive to both the HPA and HPT axis during and after C/NC stress. These neuropeptide mRNA and hnRNA levels will also be determined in executive and yoked animals pre-treated with DEX. The ability of DEX to penetrate the brain and activate glucocorticoid receptors will also be determined in executive and yoked animals. The results of these studies will fully characterize activity of both the HPA and HPT axis in executive and yoked animals, and also help elucidate the mechanisms underlying escape from DEX suppression. The effects of repeated exposure to either C/NC stress will also be determined. Changes in basal and stress-induced changes in hormone levels will be measured after 7 or 14 days of stress. Changes in neuropeptide mRNA levels will also be determined, along with measurement of Mrna encoding both glucocorticoid, mineralocorticoid, and thyroid hormone receptors. The results of these studies should provide information regarding vital neuroendocrine sytems that often become dysregulated in human depression.