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：
7526354
负责人：
KIM B SEROOGY
金额：
$ 34.13万
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/7526354
关键词：
Address Affect Affective Aging Alzheimer&apos s Disease American Animals Antidepressive Agents Apoptotic Attenuated Basal Ganglia Behavioral Behavioral Symptoms Brain Cell Death Cell Survival Cells Chemicals Chronic Chronic stress Clinical Treatment Clinical Trials Complex Condition Corpus striatum structure Depressed mood Development Disease Dopamine Elderly Endocrine Endogenous depression Etiology Experimental Parkinsonism Exposure to Fluoxetine Forelimb Functional disorder Future Gene Expression Glucocorticoid Receptor Glucocorticoids Goals High Pressure Liquid Chromatography Hippocampus (Brain)Human Imipramine Immunohistochemistry In Situ Hybridization Incidence Injection of therapeutic agent Lead Lesion Major Depressive Disorder Mediating Mental Depression Midbrain structure Modeling Moods Morbidity - disease rate Motor Movement Disorders Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurotoxins Norepinephrine Oxidopamine Parkinson Disease Parkinsonian Disorders Pathology Patients Pharmaceutical Preparations Pharmacological Treatment Predisposition Process Public Health Quality of life RU-486 Rattus Research Risk Factors Rodent Role Selective Serotonin Reuptake Inhibitor Severities Stress Symptoms System Techniques Testing Treatment Protocols Tricyclic Antidepressive Agents Tyrosine 3-Monooxygenase Work age related aged behavior test brain cell design dopaminergic neuron experience functional gain geriatric depression improved inhibitor/antagonist injured insight juvenile animal middle age neural circuit neurochemistry neuromechanism neuropsychiatry neurotoxicity neurotrophic factor novel novel therapeutics protective effect reboxetine receptor binding research study reuptake

项目摘要

DESCRIPTION (provided by applicant): 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 treatments improve or hinder 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 and apoptotic 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：抑郁症在帕金森病 (PD) 中非常普遍，通常认为抑郁症比使人衰弱的运动症状更能导致生活质量下降。尽管帕金森病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，并且可能导致新型治疗疗法的开发。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。在拟议的研究中，我们将把单侧 6-羟基多巴胺 PD 大鼠模型与广泛接受的应激性抑郁症状学大鼠模型（慢性可变应激模型）相结合，以检验实验性抑郁症加剧神经退行性变和相关功能障碍的假设。通过功能、形态、神经化学和基因表达分析评估受损的中纹状体多巴胺能系统。具体目标#1将确定神经毒素损伤之后、之前或侧面的压力诱发的抑郁是否会加剧受伤的中纹状体系统中的行为症状和多巴胺能神经元变性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神经元的存活以及PD/慢性应激诱发抑郁模型中的相关参数。具体目标#3将确定实验诱导的抑郁是否会在老年动物与年轻动物受损的中纹状体系统中更大程度地加剧行为和神经化学功能障碍以及多巴胺能神经元变性。为了测试潜在的作用机制，SPECIFIC AIM #4 将使用目前正在临床试验中治疗抑郁症的糖皮质激素受体拮抗剂，以确定压力期间释放的内源性糖皮质激素是否会介导受损的中纹状体系统中压力诱发的抑郁症的有害影响。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、酪氨酸羟化酶免疫组织化学、多巴胺及其代谢物的HPLC分析以及多巴胺相关神经营养因子和凋亡因子的原位杂交来实现。该项目的总体目标是从功能、形态和机制上深入了解帕金森病、压力和抑郁症的共病。此外，这项研究可能会带来未来缓解帕金森病情感和运动症状的疗法。公共健康相关性：几乎一半的帕金森病（美国第二常见的神经退行性疾病）患者同时患有重度抑郁症。目前的研究将调查抑郁症是否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了解这两种共病疾病中相互作用的潜在大脑回路、化学物质和机制，并可能揭示缓解帕金森病情绪和运动症状的新治疗方法。