Neurobiological Correlates of Stress and Norepinephrine Transporter

压力和去甲肾上腺素转运蛋白的神经生物学相关性

• 批准号: 7584317
• 负责人: MENG-YANG ZHU
• 金额: $ 29.24万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584317
• 关键词: Activities of Daily Living; Adrenal Glands; Affect; Amygdaloid structure; Animals; Antidepressive Agents; Area; Behavior; Binding; Biological; Brain; Brain region; Carrier Proteins; Catecholamines; Cell Line; Cell model; Cells; Chloramphenicol O-Acetyltransferase; Chronic; Chronic stress; Cognition; Corticosteroid Receptors; Corticosterone; Cultured Cells; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Disease; Dose; Electrophoretic Mobility Shift Assay; Emotions; Exposure to; Functional disorder; Gene Mutation; Genes; Genetic Transcription; Glucocorticoids; Goals; Hippocampus (Brain); Hormones; Hypothalamic structure; In Vitro; Knockout Mice; Lead; Link; Major Depressive Disorder; Measurement; Measures; Mediating; Memory; Mental disorders; Messenger RNA; Microdialysis; Modeling; Molecular; Neurobiology; Neurons; Norepinephrine; Patients; Pharmacotherapy; Phase; Pituitary Gland; Precipitation; Preventive; Proteins; Psychosocial Stress; Rattus; Regulation; Regulator Genes; Reporter; Research; Response Elements; Rodent Model; Role; Signal Pathway; Stress; Structure; Swimming; Synapses; Synaptic Cleft; System; Tail Suspension; Techniques; Testing; Therapeutic Effect; Transactivation; Transgenes; Up-Regulation; Work; base; depression; depressive symptoms; extracellular; hypothalamic-pituitary-adrenal axis; improved; in vivo; inhibitor/antagonist; innovation; locus ceruleus structure; neurotransmission; noradrenaline transporter; noradrenergic; novel; promoter; social; theories; transmission process; uptake

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.

描述（由申请人提供）：长时间的压力，通过夸张的下丘脑 - 垂体 - 肾上腺（HPA）轴作用，具有高水平的糖皮质激素，可能与抑郁症的发作有关。去甲肾上腺素能神经传递的功能障碍也被认为参与抑郁症的发展。在去甲肾上腺素能突触裂口中恢复缺乏去甲肾上腺素（NE）已被认为有助于抗抑郁药对NE转运蛋白的特异性抑制（NET）的治疗作用。然而，对压力与去肾上腺素能神经传递之间的分子相关性是抑郁症的两个潜在病因因素，对抑郁症的病因很少。压力可能会使去甲肾上腺素能系统失调，从而导致抑郁症的病理生理学。我们最近的工作表明，慢性应激显着增加了大鼠LC及其末端区域（海马和杏仁核）的净表达和功能。在大鼠和培养的细胞中也发现了类似的结果，这些细胞接受或暴露于与应力相关的皮质酮治疗。这些发现表明，压力引起的净变化可能是压力触发抑郁降水的入口点。因此，我们假设可能通过皮质酮作用的压力通过净基因的反式激活来刺激中央去甲肾上腺素能神经元中净的表达和功能。这种作用可能导致突触裂缝中NE的功能性缺乏，从而导致抑郁症中的甲肾上腺素能传播改变。在该建议中，将进行体内和体外研究以实现四个具体目标：（1）使用慢性社会失败的大鼠压力模型来评估压力对LC及其关键终端区域中净表达和功能的刺激作用； （2）使用用应力相关剂量皮质酮处理的正常大鼠阐明皮质酮对净基因的刺激作用； （3）使用培养的细胞来验证体内发现； （4）确定皮质酮调节净调控的基础机制。在所有步骤中，将评估皮质类固醇受体拮抗剂对皮质酮诱导的净调控的可能反转作用。拟议的研究将阐明应激，皮质酮和净基因以及转录机制之间的分子联系。这些发现将增强我们对抑郁症和去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。慢性压力是严重抑郁症的可能原因。在压力期间，激素（如皮质酮）的释放有所增加。这些激素在功能和结构上影响许多大脑区域。去甲肾上腺素转运蛋白是大脑中的关键蛋白质，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。该项目的目的是阐明应力，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。将使用慢性社会失败的大鼠压力模型和用皮质酮治疗的细胞模型。结果将提高我们对抑郁症和去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疗法。