Stress-Induced Depression and Parkinsonian Symptomology

压力诱发的抑郁症和帕金森病症状

基本信息

批准号：
8269921
负责人：
KIM B SEROOGY
金额：
$ 33.44万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269921
关键词：
Address Affect Affective Aging Alzheimer&apos s Disease American Animals Antidepressive Agents Attenuated Basal Ganglia Behavioral Behavioral Symptoms Brain Cell Death Cell Survival Cells Chemicals Chronic Chronic stress Clinical Data Clinical Treatment Clinical Trials Comorbidity Complex Corpus striatum structure Development Disease Dopamine Elderly Endogenous depression Enzymes Etiology Experimental Models Experimental Parkinsonism Exposure to Forelimb Functional disorder Future Gene Expression Glucocorticoid Receptor Glucocorticoids Goals High Pressure Liquid Chromatography Hippocampus (Brain)Human Immunohistochemistry In Situ Hybridization Incidence Injection of therapeutic agent Lead Lesion Major Depressive Disorder Mediating Mental Depression Midbrain structure Modeling Moods Motor Movement Disorders Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurotoxins Oxidopamine Parkinson Disease Parkinsonian Disorders Pathology Patients Peptides Pharmaceutical Preparations Pharmacological Treatment Predisposition Process Quality of life RU-486 Rattus Regimen Research Resolution Risk Factors Rodent Role Severities Stress Symptoms System Techniques Testing Tyrosine 3-Monooxygenase Work abstracting age related aged behavior test brain cell design dopaminergic neuron experience functional gain geriatric depression improved injured insight juvenile animal middle age neural circuit neurochemistry neuropsychiatry neurotoxic neurotoxicity neurotrophic factor nigrostriatal pathway novel novel therapeutic intervention receptor binding

项目摘要

Abstract Depression is a highly prevalent in Parkinson's disease (PD) and is often said to contribute more to the lowered quality 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 unilateral 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 mesostriatal dopaminergic system as evaluated by functional, morphological, neurochemical, and gene expression analyses. SPECIFIC AIM #1 will determine if stress-induced depression either following, preceding, or flanking neurotoxin lesioning exacerbates behavioral symptoms and dopaminergic neuronal degeneration and related behavioral and neurochemical sequelae in the injured mesostriatal system. SPECIFIC AIM #2 will assess whether antidepressant treatment improves or hinders midbrain dopaminergic neuron survival and associated parameters in the combined PD/chronic stress-induced depression model. SPECIFIC AIM #3 will determine if experimental induction of depression exacerbates behavioral and neurochemical dysfunction and dopaminergic neuronal degeneration to a greater extent in the injured mesostriatal system of old vs. young animals. To test a potential mechanism of action, SPECIFIC AIM #4 will use a glucocorticoid receptor antagonist currently in clinical trials for treatment of depression to determine if endogenous glucocorticoids released during stress mediate the deleterious effects of stress-induced depression in the injured mesostriatal system. In the context of the dopaminergic mesotelencephalic system, each of these aims will be addressed by using forelimb-use asymmetry behavioral tests, tyrosine hydroxylase immunohistochemistry, HPLC analysis of dopamine and its metabolites, and in situ hybridization for dopamine- associated neurotrophic factors. 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 alleviate affective as well as motor symptoms of PD. Project Narrative Almost half of all patients with Parkinson's disease, the second-most common neurodegenerative disease in the US, experience coexisting major depression. The present research will investigate whether having depression worsens motor symptoms and hastens brain cell death in PD. This work will help us understand the underlying brain circuits, chemicals and mechanisms interacting in these two co-morbid disorders and may reveal novel therapeutic approaches to relieve both mood and motor symptoms of PD.

抽象的抑郁症在帕金森病 (PD) 中非常常见，通常被认为是导致帕金森病的主要原因与衰弱的运动症状相比，生活质量降低。尽管 PD 抑郁症的病因是未知，了解潜在的病理生理过程及其有害后果合并症非常重要，可能会导致新治疗方法的开发。现在，目前缺乏旨在破译帕金森病和抑郁症复杂的神经生物学相互作用的模型。在在拟议的研究中，我们将单侧 6-羟基多巴胺 PD 大鼠模型与广泛的接受应激诱发抑郁症状的大鼠模型（慢性可变应激模型），以测试假设实验性抑郁症会加剧神经退行性变和相关的功能障碍通过功能、形态、神经化学和基因评估受损的中纹状体多巴胺能系统表达分析。具体目标#1 将确定压力诱发的抑郁症是否会出现以下情况：前面或侧面的神经毒素损伤会加剧行为症状和多巴胺能神经元受损的中纹状体系统的退化以及相关的行为和神经化学后遗症。具体目标#2将评估抗抑郁治疗是否改善或阻碍中脑多巴胺能 PD/慢性应激诱导抑郁模型中的神经元存活率和相关参数。具体目标#3将确定抑郁症的实验诱导是否会加剧行为和行为受伤者更大程度地出现神经化学功能障碍和多巴胺能神经元变性年老动物与年幼动物的中纹状体系统。为了测试潜在的作用机制，具体目标 #4 将使用目前正在进行临床试验的糖皮质激素受体拮抗剂治疗抑郁症以确定是否应激期间释放的内源性糖皮质激素介导应激引起的有害影响受损的中纹状体系统抑郁。在多巴胺能中端脑系统的背景下，这些目标中的每一个都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、多巴胺及其代谢物的 HPLC 分析以及多巴胺原位杂交相关的神经营养因子。该项目的总体目标是获得功能、形态和对帕金森病、压力和抑郁症共病的机制洞察。此外，这项研究可能会导致未来的疗法可以减轻帕金森病的情感和运动症状。项目叙述几乎一半的患者患有帕金森病，这是美国第二常见的神经退行性疾病美国经历了并存的严重萧条。本研究将调查是否有抑郁症会加重帕金森病的运动症状并加速脑细胞死亡。这项工作将帮助我们理解这两种共病疾病中潜在的大脑回路、化学物质和机制相互作用，可能揭示了缓解帕金森病情绪和运动症状的新治疗方法。