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：
7625140
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/7625140
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 Data Clinical Treatment Clinical Trials 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 Midbrain structure Modeling Moods Morbidity - disease rate 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 Research Resolution Risk Factors Rodent Role Severities Stress Symptoms System Techniques Testing Treatment Protocols Tyrosine 3-Monooxygenase Work age related aged behavior test brain cell depression 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 public health relevance receptor binding

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）：抑郁症在帕金森氏病（PD）中高度普遍，通常据说比使人衰弱的运动症状对生活质量的贡献更大。尽管PD中抑郁症的病因尚不清楚，但了解这些合并症的潜在病理生理过程和有害后果至关重要，并且可能导致新的治疗疗法的发展。目前，缺乏旨在破解PD和抑郁症的复杂神经生物学相互作用的模型。在拟议的研究中，我们将结合PD的单侧6-羟基大鼠大鼠模型与广泛接受的大鼠抑郁症状症状（慢性变化应激模型）的大鼠模型，以检验实验性抑郁症的假设，即在造成的膜神经毒素症状，使神经变性症和相关性障碍症的神经变性和相关的功能障碍促进了肌伴素促成症状，并促进了膜的功能障碍。神经化学和基因表达分析。具体目标＃1将确定压力诱导的抑郁症是否在受伤的中性层状系统中，神经毒素病变均为神经毒素病变加剧行为症状以及多巴胺能神经元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神经元的存活和相关参数，在PD/慢性应激诱导的抑郁模型中。具体的目标＃3将确定抑郁症的实验诱导是否加剧了行为和神经化学功能障碍以及多巴胺能神经元变性，在受伤的旧动物的受伤的诊断系统中，是否会更大程度地诱导。为了测试潜在的作用机理，特定的目标＃4将使用目前在临床试验中使用糖皮质激素受体拮抗剂来治疗抑郁症，以确定在压力期间释放的内源性糖皮质激素是否介导了受伤的中生系统受伤的抑郁症的有害作用。在多巴胺能中性脑脑系统的背景下，这些目标将通过使用前肢使用的不对称行为测试，酪氨酸羟化酶免疫组织化学，多巴胺及其代谢物的HPLC分析来解决这些目标，以及对多胺的原位疗法因子和养活的因子。该项目的总体目标是获得对PD，压力和抑郁症合并症的功能，形态和机械洞察力。此外，这项研究可能会导致未来减轻情感和运动症状的疗法。公共卫生相关性：在帕金森氏病的所有患者中，几乎一半是美国第二常见神经退行性疾病，经历了重大抑郁症。本研究将调查患有抑郁症是否会恶化运动症状并加速PD中的脑细胞死亡。这项工作将有助于我们了解这两种合并症中的潜在脑回路，化学物质和机制，并可能揭示出新的治疗方法，以减轻PD的情绪和运动症状。