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Ischemia-induced amnesia in rats : a neurobehavioural analysis Wood, Emma Ruth


It is well known that transient cerebral ischemia can result in irreversible neuronal damage and permanent learning and memory impairments in humans. The primary objective of this thesis was to develop a rat model of ischemia-induced amnesia that can be used both to investigate the neuropathological basis of ischemia-induced memory impairments, and to assess the ability of potential anti-ischemic drugs to prevent these impairments. First, quantitative histological techniques were used to assess the extent and location of neuronal damage produced by a bilateral carotid occlusion method of ischemia induction in rats. The neuropathological changes observed were similar to those typically associated with ischemia-induced amnesia in humans; the predominant lesion involved hippocampal CA1 pyramidal neurons, and there was no detectable extrahippocampal damage. From these results we concluded that this method of inducing ischemia is appropriate as a component of a rat model of ischemia-induced amnesia. The experiments in Chapter 3 investigated the effects of ischemia-induced brain damage in rats on their performance of nonspatial memory tasks analogous to tasks on which amnesic patients show impairments. In Experiment 3.1, rats were tested on a one-trial object recognition task that is based on the spontaneous differential exploration of novel and familiar objects. Sham-ischemia control rats spent more time investigating a novel object than a familiar object, whereas ischemic rats spent the same amount of time investigating each of the two objects. The performance of ischemic rats is consistent with a recognition memory impairment, although it may reflect a change in novelty preference. In Experiments 3.2 and 3.3, rats were tested on a delayed nonmatching-to-sample (DNMS) task that was designed to mimic the DNMS task on which monkeys and humans show deficits following ischemia. Ischemic rats were significantly impaired on DNMS compared to sham-ischemia control rats, both in learning the task and in their subsequent test performance at retention delays of 4, 15, 30, 60, 120, and 300 s. Furthermore, extensive presurgery training on DNMS did not reduce this impairment. The performance of ischemic rats on DNMS was similar to that previously reported for monkeys and humans with ischemic brain damage, indicating that ischemia-induced memory impairments are similar in rats, monkeys and humans. The experiments in Chapter 4 used the rat model of ischemia-induced amnesia to assess the therapeutic potential of a glycine receptor antagonist, both at an anatomical level, and at a behavioural level. The quantitative histological analyses performed in Experiment 4.1 showed that 7-Chlorokynurenic acid, administered immediately prior to ischemia, significantly reduced ischemic C A 1 cell loss. The preliminary behavioural analyses in Experiment 4.2 indicated that 7-Chlorokynurenic acid also attenuates the ischemia-induced DNMS impairment. On the basis of these findings, it appears that this rat model of ischemia-induced amnesia may be useful, both in the investigation of the neuropathological basis of ischemia-induced amnesia, and in the behavioural assessment of neuroprotection in ischemia.

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