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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

基本信息

批准号：
8211094
负责人：
MENG-YANG ZHU
金额：
$ 28.36万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8211094
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 Depression 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 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

项目摘要

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(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，可能与抑郁症的发生有关。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生有关。恢复去甲肾上腺素能突触间隙的去甲肾上腺素(NE)被认为有助于特异性抑制NE转运体(NET)的抗抑郁药物的治疗作用。然而，应激和去甲肾上腺素能神经传递之间的分子相关性，这两个可能导致抑郁症的因素，目前还知之甚少。应激可能导致去甲肾上腺素能系统失调，从而导致抑郁症的病理生理学改变。我们最近的工作表明，慢性应激显著增加了大鼠LC及其终末区域(海马体和杏仁核)的净表达和功能。在大鼠和培养细胞中也发现了类似的结果，这些细胞接受了与应激相关剂量的皮质酮的处理或暴露。这些发现表明，应激诱导的Net改变可能是应激触发的抑郁沉淀的入口点。因此，我们假设应激可能通过皮质酮的作用，通过反式激活Net基因来刺激中枢去甲肾上腺素能神经元Net的表达和功能。这种效应可能导致突触间隙中去甲肾上腺素的功能缺陷，从而导致抑郁症去甲肾上腺素能传递的改变。在这项建议中，将进行体内和体外研究，以实现四个特定目标：(1)使用慢性社会失败的大鼠应激模型来评估应激对LC及其关键终末区域Net表达和功能的刺激效应；(2)使用经应激相关剂量的皮质酮处理的正常大鼠来阐明皮质酮对Net基因的刺激作用；(3)使用培养细胞来验证体内的研究结果；(4)确定皮质酮调节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酮诱导的净调节的可能逆转作用。拟议的研究将阐明应激、皮质酮和net基因之间的分子联系，以及转录机制。这些发现将加深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，并最终可能导致治疗这种疾病的新药物疗法。慢性压力可能是导致严重抑郁症的原因之一。在压力下，皮质酮等荷尔蒙的释放会增加。这些荷尔蒙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大脑中的一种关键蛋白质，与控制情绪、记忆和认知的去甲肾上腺素系统的功能有关。本项目的目的是阐明应激、应激激素对去甲肾上腺素转运体的调节作用以及潜在的分子机制。将使用慢性社会挫败的大鼠应激模型和皮质酮治疗的细胞模型。这些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，并最终可能导致对这种疾病的新的药物治疗。