Stress-Induced Depression and Parkinsonian Symptomology

摘要 抑郁症是帕金森氏病(PD)中非常普遍的一种疾病，通常被认为对 比起衰弱的运动症状，生活质量更差。尽管帕金森病患者抑郁的病因是 未知，了解这些疾病的潜在病理生理过程和有害后果 合并症非常重要，并可能导致新的治疗方法的发展。目前， 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还很缺乏。在……里面 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广泛的 接受应激诱导抑郁症状的大鼠模型(慢性可变应激模型)，以测试 实验性抑郁症加剧神经变性和相关功能障碍的假说 损伤的中纹状体多巴胺能系统的功能、形态、神经化学和基因评价 表情分析。特定的目标1将确定应激诱导的抑郁是否紧随其后， 前侧或侧侧神经毒素损伤加剧行为症状和多巴胺能神经元 受损的中纹状体系统的变性和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改善还是阻碍中脑多巴胺能 帕金森病/慢性应激抑郁模型中的神经元存活及相关参数。 特定的目标#3将确定实验性的抑郁诱导是否会加剧行为和 损伤后神经化学功能障碍和多巴胺能神经元变性程度更大 老年动物与幼年动物的中纹状体系统。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 应激过程中释放的内源性糖皮质激素介导应激诱导的有害效应 受损的中纹状体系统中的抑郁。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前肢使用的不对称行为测试，酪氨酸羟化酶来实现 多巴胺及其代谢物的免疫组织化学、高效液相色谱分析和多巴胺的原位杂交 相关神经营养因子。该项目的总体目标是获得功能、形态和 对帕金森病、压力和抑郁共同发病的机械性洞察。此外，这项研究可能会导致 未来缓解帕金森病情感和运动症状的治疗方法。项目叙事 几乎一半的帕金森氏病患者，这是中国第二常见的神经退行性疾病 在美国，严重的萧条并存。本研究将调查是否有 抑郁症会加重帕金森病患者的运动症状，加速脑细胞死亡。这项工作将帮助我们理解 在这两种共病障碍中相互作用的潜在大脑回路、化学物质和机制，并可能 揭示新的治疗方法，以缓解帕金森病的情绪和运动症状。

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.