VULNERABILITY AND COMPENSATION OF DOPAMINE SYSTEMS IN ALZHEIMER'S AND AGING

多巴胺（DA）神经元系统的缺失存在于几个 老年痴呆症和正常衰老。 两种最常见的退行性疾病 老年人疾病、帕金森病（PD）和阿尔茨海默病 AD），两者都有这个系统的异常，能够产生临床 症状 DA系统的功能障碍可能会导致 各种临床症状，包括众所周知的运动异常 在PD中，还有各种认知、记忆、情感和行为 症状 黑质的神经病理学结果表明， 这些神经元的丢失程度取决于位置，色素沉着， 和投影区。 最近在啮齿动物和灵长类动物中的研究表明，DA系统是 广泛分布于大脑皮层， 海马体和杏仁核，提供了神经解剖学基础， 影响多种大脑功能。 DA功能障碍的动物模型 表明DA神经元对神经毒素的敏感性也不同 并且在不同条件下能够恢复和补偿。 本建议的初步目标是研究 两种动物DA恢复和补偿脆弱性及其机制 DA功能障碍的模型。 中纹状体和中边缘皮质 系统将被解决，以确定这些系统是否差异 影响并将这些系统与更高的大脑功能相关， 伙计 将进行初始小鼠研究以确定是否存在亚群或 DA神经元区域对神经毒素MPTP的敏感性不同。 DA指数的恢复或补偿将随着时间的推移进行审查， 模型和大鼠6-OHDA模型，以确定可能的机制， 这种补偿。 随后的研究将探讨可能 阻碍或增加追偿和赔偿形式。 大脑从 将使用各种方法分析受损动物和对照动物 技术，包括酪氨酸的原位杂交组织化学， 羟化酶（TH）、胆囊收缩素（CCK）和神经降压素（NT）基因，和 黑质（SN）/腹侧被盖区（VTA）中的神经元计数， 和DA水平，DA摄取复合物密度，酪氨酸羟化酶 纹状体投射区的活性和蛋白质水平， 海马体和大脑皮层。 这些研究的结果将有助于 指导人类死后大脑的未来研究，并可能提供 为人类干预措施的设计提供信息。 来自AD患者的脑将被分成具有以下特征的患者组： 没有锥体外系症状，而PD大脑将被分为 患有和不患有痴呆症的人群。 需要考虑的其他临床因素 分析中将包括年龄、发病年龄、疾病持续时间以及 临床严重度。 啮齿动物研究中采用的方法将是 使用，沿着额外的神经黑色素阳性计数技术 神经元和使用多个探针的可变人类TH信息， 研究类似的问题，差异DA神经元的脆弱性， 这些不同的患者群体。 将检查投影区域， 确定特定区域是否缺乏可能 与临床病理学相关。 这一目标的结果将提供 关于这些疾病的病理生理学的信息， 建议合理干预。

Abnormalities of the dopamine (DA) neuron system are present in several types of dementia and in normal aging. The two most common degenerative disorders of the elderly, Parkinson's disease (PD) and Alzheimer's disease AD), both have abnormalities of this system, capable of producing clinical symptoms. Dysfunction of the DA system has been implicated in causing a variety of clinical symptoms including the well known motor abnormalities in PD, but also a variety of cognitive, memory, affective, and behavioral symptoms. Neuropathological findings in the substantia nigra suggest that these neurons are differentially lost depending on location, pigmentation, and projection area. Recent studies in rodents and primates demonstrate that the DA system is very widely distributed in the cerebral cortex, as well as in the hippocampus and amygdala, providing a neuroanatomical substrate for influencing diverse cerebral functions. Animal models of DA dysfunction reveal that DA neurons are also differentially vulnerable to neurotoxins and are capable of recovery and compensation under different conditions. The initial objectives of this proposal are to study the differential vulnerability and mechanisms of DA recovery and compensation in two animal models of DA dysfunction. Both the mesostriatal and mesolimbocortical systems will be addressed to determine if these systems are differentially affected and relate these systems to higher cerebral functions relevant to man. Initial mouse studies will be done to determine whether subsets or regions of DA neurons are differentially sensitive to the neurotoxin MPTP. Recovery or compensation of DA indices will be examined over time in this model and in the rat 6-OHDA model to determine possible mechanisms for this compensation. Subsequent studies will address factors that may impede or augment forms of recovery and compensation. Brains from lesioned and control animals will be analyzed using a variety of techniques including in situ hybridization histochemistry for the tyrosine hydroxylase (TH), cholecystokinin (CCK), and neurotensin (NT) genes, and neuron counts in the substantia nigra (SN)/ventral tegmental area (VTA), and DA levels, density of the DA uptake complex, tyrosine hydroxylase activity and protein levels in projection areas of the striatum, hippocampus, and cerebral cortex. Results of these studies will serve to guide future studies in human postmortem brains, and may provide information for the design of interventions in man. Brains from patients with AD will be divided into groups of patients with and without extrapyramidal symptoms, while PD brains will be divided into groups with and without dementia. Other clinical factors to be considered in the analysis will include age, age of onset, duration of disease, and clinical severity. The methods employed in the rodent studies will be used, along with additional techniques of counting neuromelanin positive neurons and the use of multiple probes for the variable human TH message, to examine similar issues of differential DA neuronal vulnerability in these different patient groups. Projection areas will be examined to determined if particular area are deficient in DA markers which might correlate with clinical symptomatology. Results of this aim will provide information about the pathophysiology of these disorders, and might suggest rational interventions.