NEUROCHEMISTRY OF STRIATUM--ALTERATION BY DA DEPLETING LESIONS

本项目将重点研究儿茶酚胺的适应性。 神经元，因为它们与神经元损伤有关。我们的委托人 假设多巴胺(DA)既发挥了突触作用，又发挥了 非突触对背侧纹状体靶细胞的影响 在DA耗竭损害非突触交流和 在DA广泛丧失之前，粗大的运动行为是不存在的，而 突触交流和更微妙的运动能力 与受伤的程度大致成正比。在建议的 我们将继续对动物模型进行检验 其中含DA的投射的部分损伤 黑质纹状体通路在大鼠脑内产生 注射6-羟基多巴胺(6-OHDA)。四套 建议进行实验：首先，我们将确定 在部分丧失后，多巴胺能影响被保留 作为病变大小的函数的DA输入背侧纹状体， 术后时间及L多巴引流术的使用情况。 多巴胺对其靶点影响的神经生物学研究 完整和受损的动物包括：乙酰胆碱(Ach) 释放(D2介导的反应)，cAMP产生(主要是 和d1-响应)和GABA释放(复杂的交互作用 涉及d1和d2两个位点)。第二，我们将开展 使用行为终点的平行研究，包括食物和 水摄入量、运动活动、操作反应时间和 神经学测试电池。在第三个实验系列中，我们将 探索终端损耗和终端损耗之间差异的基础 功能缺陷，专注于病变引起的DA变化 合成、多巴胺自身受体敏感性和谷氨酸能变化 输入。最后，我们将研究与酪氨酸相关的变化 多巴胺部分损伤后羟化酶(TH)基因表达 神经元，将我们的结果与那些在响应 对去甲肾上腺素能神经元的损伤。数额上的更改 将对供应给神经末梢的TH进行检查， 航站楼内TH稳定性的变化。这一速度 还将测量TH合成，重点是TH基因的合成速度 转录和翻译。我们相信这些发现 从这项研究中发现将对 了解帕金森氏症的病因和治疗，并将 还提供了有关神经生物学的重要信息 脑内多巴胺能神经元及其与神经元的相互作用 基底节。

This project will focus on the adaptive properties of catecholamine neurons as they relate to neuronal injury. Our principal hypothesis is that dopamine (DA) exerts both a synaptic and a non-synaptic influence on target cells in the dorsal striatum and that after DA-depleting lesions non-synaptic communication and gross motor behavior is spared until DA loss is extensive, whereas synaptic communication and more subtle motoric capabilities are disrupted in rough proportion to the injury. In the proposed experiments we will continue our examination of an animal model in which partial injury of the DA-containing projections of the nigrostriatal pathway is produced in rats by the intracerebral injection of 6-hydroxydopamine (6-OHDA). Four sets of experiments are proposed: First, we will determine the extent to which a dopaminergic influence is preserved after the partial loss of the DA input to dorsal striatum as a function of lesion size, post-operative time, and the availability of L-DOPA. Neurobiological measures of the impact of DA on its targets in intact and lesioned animals will include: acetylcholine (Ach) release (a D2-mediated response), cAMP production (primarily and D1-response), and GABA release (a complex interaction involving both D1 and D2 sites). Second, we will carry out parallel studies using behavioral endpoints, including food and water intake, motor activity, operant reaction time, and a neurological test battery. In the third experimental series we will explore the basis for the discrepancies between terminal loss and functional deficits, focussing on lesion-induced changes in DA synthesis, DA autoreceptor sensitivity, and changes glutamatergic input. Finally, we will examine the changes related to tyrosine hydroxylase (TH) gene expression after partial injury of DA neurons, comparing our results from those obtained in response to damage to noradrenergic neurons. Alterations in the amount of TH supplied to the nerve terminal will be examined, as will changes in the stability of TH within the terminal. The rate of TH synthesis also will be measured, focusing on rate of TH gene transcription and translation. We believe that the findings that will emerge from this research will have implications for understanding the cause and treatment of Parkinsonism, and will also provide important information regarding the neurobiology of dopaminergic neurons and their interactions with neurons in the basal ganglia.