Neurobiological Correlates of Stress and Norepinephrine Transporter

描述（由申请人提供）：长时间的应激，通过过度的下丘脑-垂体-肾上腺（HPA）轴与高水平的糖皮质激素起作用，可能与抑郁症的发作有因果关系。去甲肾上腺素能神经传递功能障碍也被认为与抑郁症的发展有关。恢复去甲肾上腺素能突触裂隙中的去甲肾上腺素（NE）缺陷被认为有助于抗抑郁药的治疗作用，其特异性抑制NE转运蛋白（NET）。然而，压力和去甲肾上腺素能神经传递，抑郁症的两个潜在病因之间的分子相关性，知之甚少。这是可能的，压力可能失调的去甲肾上腺素能系统，从而有助于抑郁症的病理生理。我们最近的工作表明，慢性应激显着增加NET的表达和功能，在大鼠LC及其终端区域（海马和杏仁核）。在大鼠和培养的细胞中也发现了类似的结果，这些细胞被处理或暴露于压力相关剂量的皮质酮。这些研究结果表明，压力引起的NET的变化可能作为压力触发抑郁症沉淀的切入点。因此，我们推测，压力，可能通过皮质酮的作用，刺激NET的表达和功能，在中枢去甲肾上腺素能神经元的NET基因的反式激活。这种作用可能导致NE在突触裂隙中的功能缺陷，从而导致抑郁症中去甲肾上腺素能传递的改变。本研究拟通过体内和体外研究来实现以下四个具体目标：（1）利用慢性社会失败应激模型，研究应激对LC及其关键终末区NET表达和功能的刺激作用：（2）用应激相关剂量的皮质酮处理正常大鼠，研究皮质酮对NET基因的刺激作用;（3）用体外培养的细胞验证上述结果;（4）探讨皮质酮对NET的调节作用的分子机制。在所有步骤中，将评价皮质类固醇受体拮抗剂对皮质酮诱导的NET调节的可能逆转作用。这些研究将阐明应激、皮质酮和NET基因之间的分子联系以及转录机制。这些发现将增强我们对抑郁症中压力和去甲肾上腺素能功能障碍的因果作用的理解，并最终可能导致这种疾病的新药物治疗。慢性压力是导致严重抑郁症的一个可能原因。在压力下，皮质酮等激素的释放会增加。这些激素在功能和结构上影响许多大脑区域。去甲肾上腺素转运体是脑内的一种关键蛋白，与控制情绪、记忆和认知的去甲肾上腺素能系统的功能有关。本项目的目的是阐明应激、应激激素对去甲肾上腺素转运蛋白的调节作用以及潜在的分子机制。将使用慢性社交失败的大鼠应激模型和用皮质酮处理的细胞模型。这些结果将提高我们对压力和去甲肾上腺素能功能障碍在抑郁症中的因果作用的理解，并最终可能导致这种疾病的新药物治疗。

DESCRIPTION (provided by applicant): Prolonged stress, acting through the exaggerated hypothalamic-pituitary-adrenal (HPA) axis with high levels of glucocorticoids, may be causally related to the onset of depression. Dysfunction of noradrenergic neurotransmission is also thought to be involved in the development of depression. Restoring deficient norepinephrine (NE) in noradrenergic synaptic clefts has been considered to contribute to therapeutic effects of antidepressants with specific inhibition of the NE transporter (NET). However, the molecular correlation between stress and noradrenergic neurotransmission, two potential etiological factors for depression, is poorly understood. It is possible that stress may dysregulate the noradrenergic system thereby contributing to the pathophysiology of depression. Our recent work demonstrates that chronic stress significantly increases NET expression and function in the rat LC and its terminal regions (hippocampus and amygdala). Similar results are also found in rats and cultured cells, which were treated with or exposed to stress-relevant doses of corticosterone. These findings suggest that stress-induced alterations of NET may serve as the point of entry for stress-triggered precipitation of depression. Therefore, we hypothesize that stress, possibly acting through corticosterone, stimulates the expression and function of NET in central noradrenergic neurons by transactivation of the NET gene. Such an effect could result in a functional deficiency of NE in the synaptic clefts thereby contributing to altered noradrenergic transmission in depression. In this proposal, in vivo and in vitro studies will be conducted to accomplish four specific aims: (1) To use a rat stress model of chronic social defeat to assess stimulatory effects of stress on the NET expression and function in the LC and its key terminal regions; (2) To use normal rats treated with stress relevant doses of corticosterone to clarify stimulatory effects of corticosterone on the NET gene; (3) To use cultured cells to validate the in vivo findings; (4) To determine the molecular mechanisms underlying the regulation of NET by corticosterone. In all steps, possible reversed effects of the antagonists of corticosteroid receptors on corticosterone-induced NET regulation will be evaluated. The proposed studies will elucidate the molecular link between stress, corticosterone, and the NET gene, as well as the transcriptional mechanisms. The findings will augment our understanding of causal roles of stress and noradrenergic dysfunction in depression, and ultimately may lead to novel pharmacotherapies for this disease. Chronic stress is one possible cause of major depression. During stress, there is an increase in release of hormones such as corticosterone. These hormones affect many brain areas functionally and structurally. Norepinephrine transporter is a key protein in the brain and is related to the function of the noradrenergic system which controls emotion, memory and cognition. The goal of this project is to elucidate the regulatory effects of stress, stress hormones on the norepinephrine transporter, as well as underlying molecular mechanisms. A rat stress model of chronic social defeat and the cell models treated with corticosterone will be used. The results will improve our understanding of causal roles of stress and noradrenergic dysfunction in depression, and ultimately may lead to novel pharmacotherapies for this disorder.