STUDIES OF INHERITED DOPAMINE LOSS AND ANATOMICAL LOCUS

遗传性多巴胺丢失和解剖位点的研究

• 批准号: 3400403
• 负责人: SUZANNE Katherine ROFFLER-TARLOV
• 金额: $ 16.44万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3400403
• 关键词: acetylcholinesterase; autoradiography; autosomal recessive trait; brain mapping; cell migration; corpus striatum; dopamine; experimental brain lesion; genetic regulation; histochemistry /cytochemistry; innervation; mesencephalon; neuroanatomy; neurochemistry; neurotransmitters; tissue mosaicism

This proposal requests support for a combined neurochemical and histochemical study of normally innervated forebrain structures and those from a neurological mutant mouse which suffers severe depletion of dopamine. The mutant mouse to be examined is Weaver, an autosomal recessive mutation in which certain of the brain's dopamine-containing projections are altered. Preliminary work for this project suggests that the ventral and dorsal striatum of Weaver are affected differentially by this gene. The caudoputamen contains about 30% of normal dopamine content, whereas the nucleus accumbens retains normal dopamine concentrations. The first objectives of the proposed work are a) to determine by further mapping which dopamine systems in brain are affected, with special attention being paid to the nigrostriatal and mesolimbic systems, b) to establish when the targeted dopamine systems are affected and whether they die or fail to develop; and c) to examine features which distinguish the specifically targeted dopamine cells from the unaffected population. In parallel with these survey studies, an analysis will be carried out to determine the consequences of the loss of dopamine for the final organization of striatum. In particular, it is known that the striatum has a precise mosaic organization. Individual elements of the mosaic are formed by, for example, patches of low acetylcholinesterase and high opiate peptide and receptor concentrations. These mosaics are coextensive with patterns formed by other transmitter-related substances and input-output connections. The Weaver animal provides the opportunity to examine a striatum in which one component of the mosaics (that formed by the so-called dopamine islands) either never fully appears or largely disappears. The development of dopamine systems in normal and mutant mice will be followed to assess whether other neurotransmitter mosaic organizations depend upon the early-arriving dopamine fibers. These projects will involve making correlated biochemical and histochemical studies of regions of brain normally rich in dopamine, and comparing Weaver mice to controls. Some of the work will also require retrograde tracer studies and 3H-thymidine mapping. These studies should contribute to an understanding of the genetic control of the dopamine innervation of dorsal and ventral striatum and should also contribute to the understanding of the development of the patchy geometry of the striatum. The work described here has direct relevance to human diseases of the basal ganglia both acquired and genetically determined.

该提案要求支持神经化学和 正常神经支配的前脑结构的组织化学研究 来自神经突变小鼠，该小鼠严重缺乏 多巴胺。 待检查的突变小鼠是Weaver，一种常染色体 隐性突变，大脑中某些含有多巴胺的物质 预测发生改变。 该项目的初步工作表明 韦弗的腹侧和背侧纹状体受到不同的影响 这个基因。 尾壳核含有正常多巴胺含量的约30%， 而伏隔核保留正常的多巴胺浓度。 这 拟议工作的首要目标是 a) 通过进一步确定 绘制大脑中哪些多巴胺系统受到影响的图谱，并使用特殊的方法 关注黑质纹状体和中脑边缘系统，b) 确定目标多巴胺系统何时受到影响以及它们是否 死亡或无法发育； c) 检查区分的特征 专门针对未受影响人群的多巴胺细胞。 在 在进行这些调查研究的同时，还将进行一项分析 确定最终多巴胺损失的后果 纹状体的组织。 特别是，已知纹状体具有 精确的马赛克组织。 马赛克的各个元素是 例如，由低乙酰胆碱酯酶和高鸦片制剂组成的贴片 肽和受体浓度。 这些马赛克与 其他与发射体相关的物质和输入输出形成的模式 连接。 织布动物提供了检查 纹状体中，马赛克的一个组成部分（由 所谓的多巴胺岛）要么从未完全出现，要么大部分出现 消失。 正常和突变小鼠多巴胺系统的发育 随后将评估是否有其他神经递质镶嵌 组织依赖于早期到达的多巴胺纤维。 这些 项目将涉及相关生化和组织化学的制作 对通常富含多巴胺的大脑区域的研究，并与韦弗进行比较 鼠标来控制。 有些工作还需要逆行示踪剂 研究和 3H-胸苷图谱。 这些研究应该有助于 了解背侧多巴胺神经支配的遗传控制 和腹侧纹状体，也应该有助于理解 纹状体的斑块几何形状的发展。 所描述的工作 这里与基底神经节的人类疾病有直接关系 后天获得并由基因决定。