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TROPHIC FACTOR INDUCED SYNAPTIC REGROWTH IN THE CNS

营养因子诱导中枢神经系统突触再生

基本信息

批准号：
2738910
负责人：
A CLAUDIO CUELLO
金额：
$ 4.21万
依托单位：
MCGILL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 1998-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2738910
关键词：
acetylcholine age difference brain injury cerebral cortex experimental brain lesion immunocytochemistry infarct intercellular connection laboratory rat nervous system regeneration neuroprotectants neurotrophic factors nonhuman therapy evaluation synaptogenesis

项目摘要

The long term objectives of the present proposal are to determine the limits of trophic factor-induced synaptic remodelling in the cerebral cortex of lesioned animals. The proposed research addresses two key issues: (l) the extent of functional restoration in the damaged CNS and (2) the possible therapeutic use of neurotrophic factors. This research group demonstrated that, alter cortical infarct, the administration of nerve growth factor causes a regrowth of the atrophied cholinergic input to the cortex as manifested by an increase in the number of cortical cholinergic varicosities, in the size of the presynaptic elements and in the number of synaptic contacts. In the proposed research, we will address the following questions: how widespread are these changes in the cortical mantle; are they specific for the cholinergic system; does synaptic remodelling persist alter the end of therapy; can these events also be induced in the injured CNS of aged animals. These studies will be carried out in young adult and aged Fischer 344 rats. Cortical devascularizing lesions will be performed on anesthetized animals. An Alzet minipump containing either vehicle or putative neurotrophic agents (nerve growth factor and/or GM1) will be connected to a permanent cannula placed in the contralateral lateral ventricle. After one week of therapy (or longer for aged animals) the minipumps will be removed and the animals allowed to survive for various times. The cortical cholinergic fiber network will be studied by means of light and electron microscopy quantitative immunocytochemistry, with the help of image analysis. Parameters to be assessed are the density of the fiber network, the number and size of varicosities and number of synapses. These studies will be carried out in the remaining cortex, at several distances from the edge of the lesion. Furthermore, the noradrenergic and the somatostatin-immunoreactive networks will be studied in order to assess the neurochemical specificity of the neurotrophic factor induced effects on cortical synaptic circuits. Studies of the postsynaptic cholinergic targets in the remaining cortex will be carried out using double-labeling light and electron microscopic immunocytochemistry. For this purpose, choline acetyltransferase immunocytochemistry will be combined to the immunocytochemical detection of glutamate, GABA, somatostatin and VIP and the relative percentage of cholinergic synapses on each transmitter specific postsynaptic target will be assessed by quantitative electron microscopy. These studies should provide important information relevant to the issue of the potential use of neurotrophic agents to treat neurodegenerative diseases on a long term basis, on the assumption that besides the recovery of damaged perikarya, the stimulation and maintenance of neoformed synapses, as a replacement for lost circuits, is a desirable effect.

本提案的长期目标是确定脑内营养因子诱导的突触重塑的限度受损动物的皮质。这项研究提出了两个关键问题。问题：（l）受损CNS的功能恢复程度， (2)神经营养因子可能的治疗用途。本研究组证明，改变皮质梗死，神经生长因子引起萎缩的胆碱能输入的再生长大脑皮质的数量增加，胆碱能静脉曲张，在突触前元件的大小和突触接触的数量。在研究中，我们将解决以下问题：这些变化有多普遍皮质套;它们是胆碱能系统特异性的吗？治疗结束后，突触重塑持续存在;这些事件是否也可在老年动物受损的CNS中诱导。这些研究将在年轻成年和老年Fischer 344大鼠中进行。皮质将在麻醉的动物上进行血管离断损伤。一个含有载体或推定的神经营养剂的Alzet微型泵（神经生长因子和/或GM 1）将与永久性插管连接置于对侧侧脑室。经过一周的治疗 (or对于老年动物更长），将移除微型泵，动物被允许存活不同的时间。皮质胆碱能纤维网络将通过光学和电子显微镜进行研究定量免疫细胞化学，借助图像分析。待评估的参数是纤维网络的密度、纤维的密度和纤维的密度。静脉曲张的数量和大小以及突触的数量。这些研究将在剩余的皮层中进行，在几个距离病变的边缘。此外，去甲肾上腺素能和将研究生长抑素免疫反应网络，以评估神经营养因子诱导效应的神经化学特异性皮层突触回路上突触后胆碱能的研究其余皮质中的靶点将使用双标记进行光镜和电镜免疫细胞化学。为此目的，胆碱乙酰转移酶免疫细胞化学将结合到免疫细胞化学检测谷氨酸、GABA、生长抑素和VIP，每个递质上胆碱能突触的相对百分比特异性突触后靶点将通过定量电子显微镜这些研究应提供有关的重要资料神经营养剂的潜在用途，神经退行性疾病的长期基础上，假设，除了修复受损的胞体外，维持新形成的突触，作为丢失回路的替代，是一种理想的效果。