Elsevier

Neuroscience

Volume 84, Issue 3, 24 February 1998, Pages 771-781
Neuroscience

Hippocampal grafts of acetylcholine-producing cells are sufficient to improve behavioural performance following a unilateral fimbria–fornix lesion

https://doi.org/10.1016/S0306-4522(97)00543-5Get rights and content

Abstract

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.

Section snippets

Fibroblast preparation

Fibroblasts expressing either Drosophila ChAT (dChAT) or Escherichia coli LacZ (βgal) were prepared as described previously.[25]Briefly, Fischer 344 rat skin fibroblasts were infected with a retroviral vector in which the dChAT[68]or βgal transgene was expressed from the 5′ long terminal repeat promoter. The neomycin resistance gene was expressed from an internal Rous sarcoma virus promoter and the neomycin analog G418 (200 μg/ml) was used to select for stable transfectants.

Cell preparation and transplantation

Subjects were 50 male

In vitro and in vivo analysis of choline acetyltransferase activity

Expression of dChAT within transduced fibroblasts was confirmed prior to grafting by in vitro analyses of ChAT activity in cells obtained from sister flasks to those used for transplantation. The dChAT fibroblasts showed activity of 766±32.8 nmol ACh/h/mg protein, whereas fibroblasts expressing βgal had no detectable ChAT activity. To verify expression of the dChAT transgene at the conclusion of behavioural testing, in vivo assessments of ChAT activity were conducted three weeks

Discussion

In the present study, we examined the effects of ACh-producing cells implanted in the hippocampus or cortex on cognitive deficits produced by a lesion of the septohippocampal pathway. Unilateral aspirative lesions of the FFX produced significant deficits in hidden platform water maze performance without affecting swim speed, general activity, habituation or cued water maze learning. Grafts of ACh-producing fibroblasts in the denervated hippocampus significantly attenuated lesion-induced

Conclusion

In two different rat models of non-specific basal forebrain damage, tonic replacement of ACh has been shown to ameliorate water maze deficits (present results and [76]). These models mimic some of the features of cognitively-impaired aged animals in which diffuse degeneration of basal forebrain systems is prominent.2, 17, 24, 49, 58Based on the premise that ACh is vital for mnemonic functioning, augmentation of cholinergic function in the aged brain has been a focus of therapeutic strategies

Acknowledgements

We acknowledge the technical assistance of H. F. Grajeda, S. Forbes and B. Miller. This work was supported by Medical Research Council of Canada, NIA 5T32 AG00216, NIH AG10435, NIH5P01NF28121, NIHAGO8514.

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