EFFECT OF GLUCOCORTICOIDS ON MAMMALIAN TOLLOID-EXPRESSION IN THE HIPPOCAMPUS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。有机体适应环境变化以维持动态平衡的能力对生存至关重要。对这种动态平衡的威胁会导致压力，而成功地适应以对抗压力的影响会带来生存优势。应激反应部分是由下丘脑-垂体-肾上腺(HPA)轴介导的。应激事件对HPA轴的刺激会导致肾上腺皮质分泌糖皮质激素。糖皮质激素影响多种组织，使机体能够适应压力。海马神经元含有糖皮质激素受体，通过下调HPA轴对糖皮质激素水平升高做出反应。然而，慢性应激对海马神经元是有害的。糖皮质激素水平的长期升高导致树突棘的数量减少，轴突生长和突触发生减少，海马区神经发生减少。这些变化可能是慢性应激引起的疾病和障碍的基础，如创伤后应激障碍、边缘人格障碍和精神分裂症。哺乳动物类Tolloid-1(mTll-1)是一种金属蛋白酶，可增强骨形态发生蛋白(BMPs)的活性。无论是发育中的哺乳动物还是成年哺乳动物，其海马区的神经发生都需要BMP。在mTll-1的启动子中有两个可能的糖皮质激素反应元件，提示mTll-1可能受糖皮质激素的调节。MTll-1由一小部分细胞表达，这些细胞在神经发生增强的动物中增加。这项建议试图确定mTll-1的表达是否对循环中的糖皮质激素水平有反应。第一个目标是确定表达mTll-1的细胞类型。其次，应激刺激是否导致mTll-1mRNA表达的改变。第三，给予外源性糖皮质激素(皮质酮)是否会导致mTll-1mRNA表达的变化，其方式与应激刺激相似。最后，mTll-1基因表达的消融是否改变了海马齿状回内神经发生的速度？这些研究结果将为慢性应激和糖皮质激素水平升高对海马区功能的影响提供可能的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ability of an organism to adapt to changes in its environment to maintain homeostasis is critical for survival. A threat to this homeostasis results in stress and successful adaptation to counter the effects of stress confers a survival advantage. The stress response is mediated, in part, by the hypothalamic-pituitary-adrenal (HPA) axis. Stimulation of the HPA axis by a stressful event results in the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids affect a variety of tissues to enable the organism to adapt to the stress. Hippocampal neurons contain glucocorticoid receptors and respond to elevated glucocorticoid levels by downregulating the HPA axis. Chronically stress, however, is deleterious to hippocampal neurons. Chronically elevated levels of glucocorticoids result in a decrease in the number of dendritic spines, reduced axonal growth and synaptogenesis and decreased neurogenesis in the hippocampus. These changes may be the basis for diseases and disorders attributed to chronic stress, such as Post Traumatic Stress Disorder, Borderline Personality Disorder and Schizophrenia. Mammalian Tolloid-like 1 (mTll-1) is a metalloprotease that potentiates the activity of the Bone Morphogenetic Proteins (BMPs). BMPs are required for neurogenesis in the hippocampus of both developing and adult mammals. In the promoter of mTll-1 there are 2 putative glucocorticoid response element indicating that mTll-1 may be regulated by glucocorticoids. mTll-1 is expressed by a small subset of cells that increase in animals with enhanced neurogenesis. This proposal seeks to determine if mTll-1 expression is responsive to the levels of circulating glucocorticoids. The first aim will be to determine the cell type that expresses mTll-1. Secondly, does stressful stimuli result in changes in mTll-1 mRNA expression. Third, does the administration of exogenous glucocorticoids (corticosterone) result in changes in mTll-1 mRNA expression in a fashion similar to that of stressful stimuli. Finally, does the ablation of mTll-1 gene expression change the rate of neurogenesis within the dentate gyrus of the hippocampus? The results of these studies will provide a possible mechanism for the effect of chronic stress and elevated glucocorticoid levels on hippocampal function.