Nilsson O G, Brundin P, Björklund A
Department of Medical Cell Research, University of Lund, Sweden.
Brain Res. 1990 May 7;515(1-2):193-206. doi: 10.1016/0006-8993(90)90596-4.
Previous studies in the rat have shown that a serotonergic depletion greatly potentiates the learning and memory impairments produced by pharmacological or lesion-induced cholinergic blockade in the forebrain. The impairment produced by combined serotonergic-cholinergic lesions is reminiscent of that seen in memory-impaired aged rats. In the present experiment, we investigated whether grafts of cholinergic septal tissue and serotonergic mesencephalic raphe tissue, placed in the hippocampus, could reverse the severe memory impairment produced by combined cholinergic-serotonergic lesions. Adult rats were given an intraventricular injection of 5,7-dihydroxytryptamine followed by a radiofrequency lesion of the septum 1-2 weeks later. Three weeks after lesion surgery, the rats were given bilateral intrahippocampal cell suspension grafts of either fetal septal or mesencephalic raphe tissue, or both. The rats were tested for spatial learning and memory in the Morris water maze task at 4 and 10 months after grafting. At 4 months, lesioned and grafted groups were all impaired compared to the normal controls in their swim time and distance swum to find the platform, and they did not show any spatially focussed search strategy in the spatial probe trial when the platform was removed from the tank. At 10 months, the rats with mixed cholinergic and serotonergic grafts were no longer impaired compared to normals in their swim time and distance to find the platform, and they were significantly improved compared to the other grafted groups. Moreover, in the spatial probe trial, the rats with mixed cholinergic and serotonergic grafts displayed a spatially focussed search behaviour over the previous platform site, which was not seen in the lesioned control rats or in the other graft groups. Morphological analysis of the hippocampus revealed that the septal grafts produced an acetylcholinesterase-positive innervation but were totally devoid of serotonin innervation. The raphe grafts produced mainly a serotonin innervation, of both acetylcholinesterase- and serotonin-positive fibres. The results suggest that a mixture of septal and raphe tissue is required when grafted to the hippocampal formation in order to ameliorate the severe spatial learning and memory impairments produced by a combined cholinergic and serotonergic denervation, and that each of these graft types separately are not sufficient to ameliorate such deficits.
以往对大鼠的研究表明，血清素能耗竭会极大地增强由药理学方法或在前脑进行损伤诱导的胆碱能阻断所产生的学习和记忆障碍。血清素能 - 胆碱能联合损伤所产生的障碍类似于在记忆受损的老年大鼠中所观察到的情况。在本实验中，我们研究了植入海马体的胆碱能隔区组织和血清素能中脑缝际组织移植是否能够逆转由胆碱能 - 血清素能联合损伤所导致的严重记忆障碍。成年大鼠脑室内注射5,7 - 二羟基色胺，1 - 2周后对隔区进行射频损伤。损伤手术后三周，给大鼠双侧海马内注射胎儿隔区或中脑缝际组织的细胞悬液移植，或者两者都注射。在移植后4个月和10个月时，对大鼠进行莫里斯水迷宫任务中的空间学习和记忆测试。在4个月时，与正常对照组相比，损伤组和移植组在寻找平台的游泳时间和游动距离上均受损，并且在空间探索试验中，当平台从水箱中移除时，它们没有表现出任何空间聚焦的搜索策略。在10个月时，与正常组相比，接受胆碱能和血清素能混合移植的大鼠在寻找平台的游泳时间和距离上不再受损，并且与其他移植组相比有显著改善。此外，在空间探索试验中，接受胆碱能和血清素能混合移植的大鼠在先前平台位置表现出空间聚焦的搜索行为，而在损伤对照组大鼠或其他移植组中未观察到这种行为。海马体的形态学分析显示，隔区移植产生了乙酰胆碱酯酶阳性的神经支配，但完全没有血清素神经支配。缝际移植主要产生血清素神经支配，包括乙酰胆碱酯酶阳性和血清素阳性纤维。结果表明，当移植到海马结构时，需要隔区和缝际组织的混合物才能改善由胆碱能和血清素能联合去神经支配所产生的严重空间学习和记忆障碍，并且单独的每种移植类型不足以改善此类缺陷。
