Glucocorticoid Mechanisms of Stress-Induced Depression and Parkinsonian Symptomol

应激性抑郁和帕金森症状的糖皮质激素机制

• 批准号: 8532057
• 负责人: KIM B SEROOGY
• 金额: $ 6.67万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8532057
• 关键词: Address; Affect; Affective Symptoms; Aging; American; Behavioral; Cell Death; Cells; Chronic; Chronic stress; Clinical Treatment; Clinical Trials; Comorbidity; Complex; Corticosterone; Custom; Data; Development; Disease; Disease model; Dopamine; Endogenous depression; Etiology; Experimental Models; Exposure to; Forelimb; Functional disorder; Future; Gene Expression; Glucocorticoid Receptor; Glucocorticoids; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Hormones; Incidence; Individual; Lead; Lesion; Life; Major Depressive Disorder; Mental Depression; Modeling; Molecular; Moods; Motor; Movement Disorders; Nerve Degeneration; Neurobiology; Neurologic; Neurons; Neurotoxins; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Physiological; Process; Quality of life; RU-486; Rattus; Recruitment Activity; Regimen; Research; Research Personnel; Rodent; Stress; Symptoms; Syndrome; System; Testing; Therapeutic; Therapeutic Intervention; Tyrosine 3-Monooxygenase; Work; age related neurodegeneration; base; behavior test; density; dopamine system; experience; functional gain; improved; injured; insight; motor deficit; neural circuit; neurochemistry; neurotoxicity; nigrostriatal pathway; nigrostriatal system; novel; novel therapeutic intervention; programs; receptor binding; response; stressor

Depression is a highly prevalent in Parkinson's disease (PD) and is often said to contribute more to the lowered quaUty of life than the debilitating motor symptoms. Although the etiology of depression in PD is unknown, understanding the potential pathophysiological processes and deleterious consequences of these co-morbidities is of high importance, and may lead to the development of novel treatment therapies. Currently, models aimed at deciphering the complex neurobiological interactions of PD and depression are lacking. In the proposed studies, we will combine the intrastriatal 6-hydroxydopamine rat model of PD with a widely accepted rat model of stress-induced depression symptomology (chronic variable stress model), to test the hypothesis that experimental depression exacerbates the neurodegeneration and associated dysfunction of the injured nigrostriatal dopaminergic system via deleterious glucocorticoid mechanisms as evaluated by functional, morphological, neurochemical, and gene expression analyses. To test potential mechanisms by which depression may increase nigrostriatal vulnerability, SPECIFIC AIM #1 will evaluate the necessity and sufficiency of glucocorticoids in dopaminergic degeneration and motor dysfimction, and determine plausible molecular correlates contributing to the enhanced degeneration. In the context of the dopaminergic mesotelencephalic system, these aims will be addressed by using forelimb-use asymmetry behavioral tests, tyrosine hydroxylase immimohistochemistry, unbiased stereology, HPLC analysis of dopamine and its metabolites, and custom PCR arrays. The overall goal of this project is to gain functional, morphological and mechanistic insight into the co-morbidity of PD, stress and depression. Moreover, this research may lead to future therapies that ameliorate alTective as well as motor symptoms of PD. RELEVANCE (See instmctions): Almost half of all patients with Parkinson's disease experience coexisting major depression. The present research will investigate whether having abnormal levels of stress hormones is a mechanism by which depression worsens motor symptoms and accelerates nerve cell death in PD. This work will help us understand the underlying mechanisms interacting in these two co-morbid disorders and may reveal novel therapeutic approaches to relieve both mood and motor symptoms of PD.

抑郁症在帕金森病 (PD) 中非常常见，通常被认为是导致质量下降的主要原因 与使人衰弱的运动症状相比，对生命的影响更大。尽管 PD 抑郁症的病因尚不清楚，但了解 这些共病的潜在病理生理过程和有害后果非常重要，并且 可能会导致新的治疗方法的开发。目前，旨在破译复杂的模型 PD 和抑郁症之间的神经生物学相互作用尚缺乏。在拟议的研究中，我们将结合纹状体内 6-羟基多巴胺 PD 大鼠模型，具有广泛接受的应激性抑郁症状大鼠模型 （慢性可变压力模型），检验实验性抑郁症加剧神经退行性变的假设 以及通过有害的糖皮质激素机制导致受损的黑质纹状体多巴胺能系统的相关功能障碍 通过功能、形态、神经化学和基因表达分析进行评估。测试潜在机制 抑郁症可能会增加黑质纹状体的脆弱性，具体目标#1将评估必要性和 糖皮质激素在多巴胺能变性和运动功能障碍中的充足性，并确定合理的分子 与加剧退化相关。在多巴胺能中端脑系统的背景下， 这些目标将通过使用前肢使用不对称行为测试、酪氨酸羟化酶来实现 免疫组织化学、无偏立体学、多巴胺及其代谢物的 HPLC 分析以及定制 PCR 阵列。 该项目的总体目标是从功能、形态和机制方面深入了解 PD、压力和抑郁。此外，这项研究可能会带来未来的治疗方法，改善 aTective 以及 PD 的运动症状。 相关性（参见说明）： 几乎一半的帕金森病患者同时患有重度抑郁症。现在的 研究将调查应激激素水平异常是否是一种机制 抑郁会加重帕金森病的运动症状并加速神经细胞死亡。这项工作将帮助我们 了解这两种共病疾病相互作用的潜在机制，并可能揭示新的 缓解帕金森病情绪和运动症状的治疗方法。