Stress-Induced Depression and Parkinsonian Symptomology

描述(由申请人提供)：抑郁症是帕金森氏病(PD)中非常普遍的一种疾病，经常被认为比使人虚弱的运动症状更能导致生活质量下降。虽然帕金森病患者抑郁的病因尚不清楚，但了解这些共病的潜在病理生理过程和有害后果是非常重要的，并可能导致新的治疗方法的发展。目前，缺乏旨在破译帕金森病和抑郁症之间复杂的神经生物学相互作用的模型。在拟议的研究中，我们将结合单侧6-羟基多巴胺大鼠帕金森病模型和被广泛接受的应激诱导抑郁症状学大鼠模型(慢性可变应激模型)，通过功能、形态、神经化学和基因表达分析来验证实验性抑郁加剧受损的中纹状体多巴胺能系统的神经退化和相关功能障碍的假设。特定的目标1将确定在神经毒素损毁之后、之前或两侧的应激性抑郁是否会加剧受损的中纹状体系统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。特定的AIM#2将评估抗抑郁治疗是否改善或阻碍了帕金森病/慢性应激诱导的抑郁模型中中脑多巴胺能神经元的存活和相关参数。具体目的#3将确定实验性抑郁诱导是否会在更大程度上加剧老年动物和幼年动物受损的中纹状体系统中的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，特定的AIM#4将使用目前正在进行的治疗抑郁症的临床试验中的糖皮质激素受体拮抗剂来确定在应激期间释放的内源性糖皮质激素是否介导了应激诱导的抑郁在受损的中纹状体系统中的有害影响。在多巴胺能中脑系统的背景下，将通过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高效液相色谱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这些目标。这个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、应激和抑郁的共同发病率。此外，这项研究可能会导致未来的治疗方法，以缓解情感和运动症状的帕金森病。公共卫生相关性：帕金森氏症是美国第二常见的神经退行性疾病，几乎一半的患者都患有严重的抑郁症。目前的研究将调查抑郁是否会恶化帕金森病患者的运动症状并加速脑细胞死亡。这项工作将有助于我们了解这两种共病疾病中潜在的大脑回路、化学物质和相互作用的机制，并可能揭示缓解帕金森病情绪和运动症状的新的治疗方法。

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.