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A reexamination of the role of the hippocampus in object-recognition memory using neurotoxic lesions and ischemia in rats

University of British Columbia

Paradoxical results on object-recognition delayed nonmatching-to-sample (DNMS) tasks have been found in monkeys and rats that receive either partial, ischemia-induced hippocampal lesions or complete hippocampal ablation. Ischemia results in severe DNMS impairments, which have been attributed to circumscribed CA1 cell loss. However, ablation studies indicate that the hippocampus plays only a minimal role in the performance of the DNMS task. Two hypotheses have been proposed to account for these discrepant findings (Bachevalier & Mishkin, 1989). First, the "hippocampal interference" hypothesis posits that following ischemia, the partially damaged hippocampus may disrupt activity in extrahippocampal structures that are important for object-recognition memory. Second, previously undetected ischemia-induced extrahippocampal damage may be responsible for the DNMS impairments attributed to CA1 cell loss. To test the "hippocampal interference" hypothesis, the effect of partial NMDAinduced lesions of the dorsal hippocampus were investigated on DNMS performance in rats. These lesions damaged much of the same area, the CA1, as did ischemia; but did so without depriving the entire forebrain of oxygen, thereby reducing the possibility of extrahippocampal damage. In Experiment 1, rats were trained on the DNMS task prior to receiving an NMDA-lesion. Postoperatively, these rats reacquired the nonmatching rule at a rate equivalent to controls and were unimpaired in performance at delays up to 300 s. In Experiment 2, naive rats were given NMDA-lesions and then trained on DNMS. These rats acquired the DNMS rule at a rate equivalent to controls and performed normally at delays up to 300 s. These findings suggest that interference from a partially damaged hippocampus cannot account for the ischemia-induced DNMS impairments and that they are more likely produced by extrahippocampal neuropathology. In Experiment 3, rats from the previous study were tested on the Morris water-maze. Compared to sham-lesioned animals, rats with partial lesions of the dorsal hippocampus were impaired in the acquisition of the water-maze task. Thus, subtotal NMDA-lesions of the hippocampus impaired spatial memory while leaving nonspatial memory intact. Mumby et al. (1992b) suggested that the ischemia-induced extrahippocampal damage underlying the DNMS deficits is mediated or produced by the postischemic hippocampus. To test this idea, preoperatively trained rats in Experiment 4 were subject to cerebral ischemia followed within 1hr by hippocampal aspiration lesions. It was hypothesized that ablation soon after ischemia would block the damage putatively produced by the postischemic hippocampus and thereby prevent the development of postoperative DNMS deficits. Unlike "ischemia-only" rats, the rats with the combined lesion were able to reacquire the nonmatching rule at a normal rate and performed normally at delays up to 300 s. Thus, hippocampectomy soon after ischemia eliminated the pathogenic process that lead to ischemia-induced DNMS deficits. Experiment 5 investigated the role of ischemiainduced CA1 cell death as a factor in the production of extrahippocampal neuropathology. Naive rats were given NMDA-lesions of the dorsal hippocampus followed 3 weeks later by cerebral ischemia. If the ischemia-induced CA1 neurotoxicity is responsible for producing extrahippocampal damage then preischemic ablation should attenuate this process and prevent the development of DNMS impairments. This did not occur: Rats with the combined lesion were as impaired as the "ischemia-only" rats in the acquisition of the DNMS task. This suggests that the ischemia-induced pathogenic processes that result in extrahippocampal neuropathology comprise more than CA1 neurotoxicity. The findings presented in this thesis are consistent with the idea that ischemiainduced DNMS deficits in rats are the result of extrahippocampal damage mediated or produced by the postischemic hippocampus. The discussion focuses on three main points: 1) How might the post-ischemic hippocampus be involved in the production of extrahippocampal neuropathology? 2) In what brain region(s) might this damage be occurring? 3) What anatomical, molecular, or functional neuropathology might ischemia produce in extrahippocampal brain regions? The results are also discussed in terms of a specialized role for the hippocampus in mnemonic functions and the recently emphasized importance of the rhinal cortex in object-recognition memory.

Thesis/Dissertation

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2009-03-19

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http://hdl.handle.net/2429/6240

Psychology

University of British Columbia

UBCV

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