Stress-Induced Depression and Parkinsonian Symptomology

描述（由申请人提供）：抑郁症在帕金森病（PD）中非常普遍，并且通常被认为比使人衰弱的运动症状更有助于降低生活质量。虽然PD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非常重要，并可能导致开发新的治疗方法。目前，缺乏旨在破译PD和抑郁症复杂神经生物学相互作用的模型。在拟议的研究中，我们将结合联合收割机单侧6-羟基多巴胺大鼠模型PD与广泛接受的大鼠模型应激诱导的抑郁症病理学（慢性可变应激模型），以测试的假设，即实验性抑郁症加剧了受损的中纹状体多巴胺能系统的神经变性和相关功能障碍的功能，形态，神经化学和基因表达分析评估。具体目标#1将确定在神经毒素损伤之后、之前或两侧的应激诱导的抑郁症是否会加重受损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将评估抗抑郁药治疗是否改善或阻碍组合PD/慢性应激诱导的抑郁模型中的中脑多巴胺能神经元存活和相关参数。具体目标#3将确定实验性诱导抑郁是否在老年动物与年轻动物的受损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将使用目前在临床试验中用于治疗抑郁症的糖皮质激素受体拮抗剂，以确定在应激期间释放的内源性糖皮质激素是否介导损伤的中纹状体系统中应激诱导的抑郁症的有害作用。在多巴胺能中脑系统的背景下，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，多巴胺及其代谢产物的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解决。该项目的总体目标是获得功能，形态和机制的洞察PD，压力和抑郁症的共病。此外，这项研究可能会导致未来的治疗，减轻情感以及运动症状的PD。 公共卫生相关性：几乎一半的帕金森病患者，美国第二常见的神经退行性疾病，经历共存的重度抑郁症。本研究将探讨抑郁是否会减轻帕金森病患者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脑回路、化学物质和机制，并可能揭示缓解PD情绪和运动症状的新治疗方法。

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.