Glucocorticoid & corticosteriod receptor-dependence of HPA activity and behavior

描述（由申请人提供）：使用升高的HPA活性作为抑郁症的生物标志物受到HPA活性、情绪和抗抑郁（AD）作用之间关系的不确定性的限制。抑郁症中HPA活性增加归因于糖皮质激素反馈抑制受损，可通过抗抑郁药诱导的脑糖皮质激素（GR）和盐皮质激素（MR）受体增加来纠正。然而，抗糖皮质激素治疗对一些抑郁症患者的益处表明，增加GR或MR可能不需要或不适合抗抑郁作用，并进一步表明，通过增加糖皮质激素，HPA活性升高可能是抑郁症的原因，以及标志物。为了区分糖皮质激素水平的增加，从减少的作用，在HPA相关的抑郁症的病理，本建议使用前脑GR基因敲除（FBGRKO）小鼠，HPA多动性抑郁症的模型，以测试的假设，即基础和抗抑郁药诱导的抑郁行为的变化取决于糖皮质激素分泌的变化。目的明确基础和应激诱导的HPA活性与急性和慢性抗抑郁作用的关系，以确定糖皮质激素和抗抑郁作用的检测条件。目的II将通过测试肾上腺切除术和固定的糖皮质激素替代是否使FBGRKO小鼠的抑郁样行为正常化来确定糖皮质激素对基础行为的影响。目的III将通过使用肾上腺切除的FBGRKO和floxed GR对照（有和没有固定的糖皮质激素替代）来确定糖皮质激素在抗抑郁作用中的作用，以测试长期抗抑郁治疗是否独立于糖皮质激素的变化而使行为和下丘脑-垂体活动正常化。这些研究解决了长期存在的理论和矛盾的作用，皮质类固醇受体和糖皮质激素在抑郁症。这项工作确定的前脑GR和糖皮质激素独立的影响可以解释抗抑郁药如何使抑郁症中升高的HPA活性正常化，而不会促进糖皮质激素对情绪的不良影响。这些信息可用于更准确地预测和监测HPA多动性抑郁症的抗抑郁反应。 该项目将确定肾上腺糖皮质激素（通常在抑郁症中增加）是否可能导致抑郁症症状并影响抗抑郁作用。这些信息可以帮助确定更有效的抗抑郁药，用于糖皮质激素水平异常的抑郁症患者，并设计更准确地检测抗抑郁反应的激素测试。由于抑郁症的恢复取决于早期有效的治疗，这项工作的结果可以通过最大限度地提高初始治疗的成功率，最终降低抑郁症的公共卫生成本。

DESCRIPTION (provided by applicant): The use of elevated HPA activity as a biomarker for depression is limited by uncertainty as to the relationship between HPA activity, mood, and antidepressant (AD) effects. Increased HPA activity in depression has been attributed to impaired glucocorticoid feedback inhibition that can be corrected by antidepressant-induced increases in brain glucocorticoid (GR) and mineralocorticoid (MR) receptors. However, benefits to some depressed patients from antiglucocorticoid therapies suggest that increasing GR or MR may not be required or appropriate for antidepressant action, and further suggest that by increasing glucocorticoids, elevated HPA activity might be a cause, as well as a marker, of depression. To discriminate the role of decreased GR from that of increased glucocorticoid levels in HPA-related depression pathology, this proposal uses forebrain GR knockout (FBGRKO) mice, a model of HPA-hyperactive depression, to test the hypothesis that that basal and antidepressant-induced changes in depression behaviors depend on changes in glucocorticoid secretion. Aim I will define the relationship of basal and stress-induced HPA activity to acute and chronic antidepressant actions to identify conditions for testing glucocorticoid and antidepressant effects. Aim II will determine glucocorticoid effects on basal behavior by testing if adrenalectomy and fixed glucocorticoid replacement normalizes depression-like behavior in FBGRKO mice. Aim III will determine the role of glucocorticoids in antidepressant action by using adrenalectomized FBGRKO and floxed GR controls with and without fixed glucocorticoid replacement to test if chronic antidepressant treatment normalizes behavior and hypothalamic- pituitary activity independently of changes in glucocorticoids. These studies address long-standing theories and contradictions of the roles of corticosteroid receptors and glucocorticoids in depression. Forebrain GR- and glucocorticoid-independent effects identified by this work could explain how antidepressants normalize elevated HPA activity in depression without facilitating adverse glucocorticoid effects on mood. This information could be used to predict and monitor antidepressant response more accurately in HPA-hyperactive depression. PUBLIC HEALTH RELEVANCE This project will determine if adrenal glucocorticoid hormones, which often increase in depression, might contribute to depression symptoms and influence antidepressant effects. This information could help to identify more effective antidepressants for depressed patients with abnormal glucocorticoid levels and to design hormone tests that detect antidepressant response more accurately. Since depression recovery depends on early effective treatment, results from this work could ultimately reduce the public health costs of depression by maximizing initial treatment success.