Research reportEffects of cytotoxic hippocampal lesions in mice on a cognitive test battery
Introduction
The effects of hippocampal lesions in animals have been extensively studied, and one of the clearest results is a deficit in spatial learning [29]. The majority of these studies, however, employed rats, and many were performed using aspiration or electrolytic lesions, before the advent of the more selective cytotoxic techniques [19]. Relatively few studies have employed mice with cytotoxic lesions, but they too generally report spatial learning deficits [1], [3], [4], [13], [23]. The aim of the present studies was the analysis of the effects of cytotoxic hippocampal lesions in mice, and the identification of testing procedures suitable for this species. Results from a novel spatial task similar to the Morris water maze, the paddling pool, are reported elsewhere [8].
Traditionally, the rat has been the species most often used in behavioural research. Rats were, and still are, generally considered to be more amenable to work with in most behavioural tasks. They are generally reputed, whether warranted or not, to be more adaptable and consistent in their behaviour than mice. Mice are increasingly being used in behavioural research, however, as most genetic manipulations employ this species. An increasing number of publications are comparing the behaviour of mutant mice on tasks considered to be hippocampal dependent or independent [22], yet the basic experiments on the behavioural effects of brain lesions, on which the interpretation of these mouse results depends, have largely been performed in rats. In many instances the two species indeed show a similar neuropsychological profile, but on occasion discrepancies appear. For instance, hippocampal lesions in rats can increase food hoarding, whereas in mice they decrease it [7]. Contextual fear conditioning has been cited as another example where hippocampal lesions may be less effective in mice than rats [1], [3], [11], although these alleged species differences may also have been due in part to incomplete removal of the ventral hippocampus, which in rats has been shown to be necessary for normal acquisition of contextually conditioned freezing [37]. The present study aimed to characterise the effects of hippocampal lesions in mice on performance in a variety of cognitive tasks, partly to provide a foundation for interpreting more specific, molecular genetic, interventions. All testing was performed post-operatively. Unless a temporally conditional knock-out model is employed, mutant mice are necessarily tested ‘post-operatively’.
The lesioned mice were given a variety of general behaviour and sensorimotor tests, the purpose of which was to eliminate the possibility that any cognitive deficits could be due to non-specific performance deficits [6], [7]. They were then tested on a variety of cognitive tasks, employing appetitive and exploratory motivation, two types of aversive motivation (deep or shallow water, electric foot-shock), and spatial and non-spatial cues (the categories are not mutually exclusive). The aim was to reveal any lesion-induced cognitive deficits and clarify their nature.
The C57BL/6J strain was used, as this is one of the most widely used in behavioural work and is used in the production of many models in behavioural genetics [5], [6], [10]. Female mice were used, partly as they can be group housed for long periods without the risk of severe fighting in this strain. Moreover, group housing reduces stress in social animals.
Section snippets
Subjects
Female C57BL/6J mice (Harlan UK) arrived in the laboratory at 9 weeks old (15–21 g), and were housed on a 12-h light:12-h dark cycle (lights on at 07:00 h) in groups of four in plastic cages, with wood shaving bedding and a cardboard tube to provide some environmental enrichment. Behavioral testing was performed during the light phase. Food and water were ad libitum, except during training on the appetitively motivated tasks (T-maze non-matching to sample, Y-maze and Lashley maze). For these,
Working memory: spontaneous alternation, T-maze
Spontaneous alternation levels were at chance for the hippocampal group. The controls scored a median 80.0% correct, hippocampals 50.0%, T=204, P<0.0001, Mann–Whitney test.
Working memory: spontaneous alternation, Y-maze
Control performance was poor, only just above chance, and similar to the lesioned group. Controls scored a median 56.0% correct, hippocampals 52.6%, T=138, P=0.977, Mann–Whitney test. There was a tendency for the lesioned group to have a greater direction bias than the controls; the bias ratios were 0.173 and 0.085,
Working memory: spontaneous alternation, T-maze
The hippocampal mice showed the classic lesion-induced impairment on this task, first noted in rats [38]. This established the functional effectiveness of the lesions, and further testing in the other paradigms confirmed that this deficit was indeed due to a deficit in spatial cognition, rather than ancillary factors.
Working memory: spontaneous alternation, Y-maze
The lesioned mice showed low rates of alternation but so did the controls. Continuous alternation paradigms often yield lower performance than discrete-trial alternation, in both
Acknowledgements
This work was supported by a Wellcome Trust project grant, no. 060321. Greg Daubney ably performed the histological processing.
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