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）：长期的压力，通过夸大的下丘脑-垂体-肾上腺（HPA）轴和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。在去甲肾上腺素能突触间隙中恢复缺乏的去甲肾上腺素（NE）被认为有助于抗抑郁药特异性抑制NE转运体（NET）的治疗效果。然而，应激和去甲肾上腺素能神经传递这两种抑郁症的潜在病因之间的分子相关性尚不清楚。压力可能会使去肾上腺素能系统失调，从而导致抑郁症的病理生理。我们最近的研究表明，慢性应激显著增加大鼠LC及其末端区域（海马和杏仁核）的NET表达和功能。在大鼠和培养细胞中也发现了类似的结果，这些细胞使用或暴露于与压力相关的皮质酮剂量。这些发现表明，应激诱导的NET改变可能是应激引发抑郁沉淀的切入点。因此，我们假设应激可能通过皮质酮作用，通过NET基因的反激活刺激中枢去肾上腺素能神经元中NET的表达和功能。这种效应可能导致突触间隙中NE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。本课题将开展体内和体外研究，以实现以下四个具体目标：(1)利用大鼠慢性社会失败应激模型，评估应激对LC及其关键末端区域NET表达和功能的刺激作用；(2)用应激相关剂量皮质酮处理正常大鼠，阐明皮质酮对NET基因的刺激作用；(3)利用培养细胞验证体内研究结果；(4)确定皮质酮调控NET的分子机制。在所有步骤中，将评估皮质类固醇受体拮抗剂对皮质类固醇诱导的NET调节可能产生的逆转作用。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。这些发现将增加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。慢性压力是导致重度抑郁症的一个可能原因。在压力下，皮质醇等激素的释放会增加。这些激素在功能和结构上影响大脑的许多区域。去甲肾上腺素转运蛋白是大脑中的一种关键蛋白，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。本项目旨在阐明应激、应激激素对去甲肾上腺素转运体的调控作用及其潜在的分子机制。将采用大鼠慢性社会失败应激模型和皮质酮处理的细胞模型。该结果将提高我们对应激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。