Dickinson-Anson H, Aubert I, Gage F H, Fisher L J
Laboratory of Genetics, The Salk Institute, La Jolla, CA 92037, USA.
Neuroscience. 1998 Jun;84(3):771-81. doi: 10.1016/s0306-4522(97)00543-5.
Lesions of the septohippocampal pathway produce cognitive deficits that are partially attenuated by grafts of cholinergic-rich tissue into denervated target regions or by systemic administration of cholinomimetic drugs. In the present study, fibroblasts engineered to produce acetylcholine were used to test the hypothesis that restoration of hippocampal acetylcholine in rats with septohippocampal lesions is sufficient to improve cognitive processing post-damage. Rats received unilateral grafts of acetylcholine-producing or control fibroblasts into the hippocampus immediately prior to an aspirative lesion of the ipsilateral fimbria-fornix. Some rats with fimbria-fornix lesions were implanted with acetylcholine-producing or control fibroblasts into the neocortex, another major target of the basal forebrain cholinergic system, to determine if the site of acetylcholine delivery to the damaged brain is critical for functional recovery. Rats were tested in a hidden platform water maze task, a cued water maze task and activity chambers between one and three weeks post-grafting. Compared to unoperated controls, rats with fimbria fornix lesions only were significantly impaired in hidden platform water maze performance. Hippocampal grafts of acetylcholine-producing cells reduced lesion-induced deficits in the water maze, whereas hippocampal control grafts and cortical grafts of either cell type were without effect. Locomotor activity and cued water maze performance were unaffected by the lesion or the implants. Taken together, these data indicate that water maze deficits produced by fimbria fornix lesions, which disrupt a number of hippocampal neurotransmitter systems, can be attenuated by target specific replacement of acetylcholine in the hippocampus and that this recovery occurs in the absence of circuitry repair.
隔海马通路损伤会导致认知缺陷，而向去神经支配的靶区域移植富含胆碱能的组织或全身给予拟胆碱药物可部分减轻这些缺陷。在本研究中，经基因工程改造能产生乙酰胆碱的成纤维细胞被用于检验以下假设：在患有隔海马损伤的大鼠中，恢复海马中的乙酰胆碱足以改善损伤后的认知加工。大鼠在同侧穹窿海马伞进行抽吸损伤之前，立即将产生乙酰胆碱的或对照成纤维细胞单侧移植到海马中。一些患有穹窿海马伞损伤的大鼠将产生乙酰胆碱的或对照成纤维细胞植入新皮层，新皮层是基底前脑胆碱能系统的另一个主要靶区，以确定将乙酰胆碱输送到受损大脑的部位对功能恢复是否至关重要。在移植后1至3周期间，对大鼠进行隐藏平台水迷宫任务、线索水迷宫任务和活动箱测试。与未手术的对照组相比，仅患有穹窿海马伞损伤的大鼠在隐藏平台水迷宫任务中的表现明显受损。移植产生乙酰胆碱的细胞可减少水迷宫中损伤诱导的缺陷，而海马对照移植以及两种细胞类型的皮层移植均无效果。损伤或植入物对运动活动和线索水迷宫任务表现没有影响。综上所述，这些数据表明，由穹窿海马伞损伤导致的水迷宫缺陷（该损伤破坏了多个海马神经递质系统）可通过在海马中进行靶特异性乙酰胆碱替代来减轻，并且这种恢复是在没有神经回路修复的情况下发生的。
