Hippocampal lesions, species-typical behaviours and anxiety in mice

Abstract

The hippocampus is believed to play an important role in spatial cognition and anxiety. Much of the supporting evidence is derived from rat studies. Recent reports on hippocampal lesioned mice also showed impairments in spatial function, but anxiety was not uniformly diminished. There were, however, striking impairments in several “species typical” behaviours; lesioned mice made poorer nests, and hoarded and burrowed less. In the present experiments, mice with excitotoxic hippocampal lesions were tested in a well-established anxiety paradigm, the light–dark box. As in previous anxiety tests, the results were mixed; some measures (reduced dark time) suggested lesioned mice were less anxious; others (fewer light–dark transits) suggested greater anxiety. However, lesioned mice only made fewer transits when the door was small. This suggested that the tendency to enter small holes, so characteristic of small rodents, was reduced; subsequent tests showed lesioned mice preferred to explore in an alley rather than enter its attached tunnels. Further tests of “species typical” behaviours revealed that lesioned mice spent less time digging and climbing, and made less use of cardboard shelters in their cages. This was not due to inactivity; lesions did not reduce grooming or locomotion. Finally, tests of hyponeophagia showed hippocampal lesions reduced this measure of anxiety, so long as the control baseline was sufficiently high. Overall, the results suggest that the hippocampus is important in many species-typical behaviours, potentially influencing performance in a range of behavioural tests. However, species-typical behaviours offer easy and economical ways to test for hippocampal dysfunction, for example, in genetically modified mice.

Introduction

A substantial body of evidence from rat studies suggests that the hippocampus plays a crucial role in spatial cognition [2], [4], [23], [24]. Recent work from this laboratory has shown that mice with large cytotoxic lesions of the hippocampus also show pronounced deficits in spatial learning [10], [14], [27], [29]. An alternative view of hippocampal function is that it is part of a brain system underlying emotional behaviour [19]. Again, much of the data derives from rat studies (e.g. [2], [3], [11], [22]). When tests of emotional behaviour in hippocampectomised mice were performed, however, the results were less clear [12]. Lesioned mice were often slower to enter the more anxiogenic regions of the apparatus, such as the open arms of the plus-maze, although once there they generally stayed longer. Surprisingly, and in disagreement with experiments on rats [11], they were not faster to consume a novel food in a novel place, i.e. they did not show reduced hyponeophagia. One explanation for these mixed effects on anxiety measures might be that the lesions were inhibiting species-typical behaviours on which performance of particular tests depends. Ethological tests of anxiety depend on the expression of species-typical behaviours. If these underlying behaviours are disrupted by hippocampal dysfunction then some measures of anxiety would be selectively distorted as a result.

There was indeed clear evidence that some species-typical behaviours were affected by hippocampal damage. Lesioned mice made poorer nests, dug (burrowed) less material from a tube, hoarded less food, reared less in an open field, made fewer head dips in a holeboard and explored the edges of their cages less [12]. O’Keefe and Nadel [24] note that species-typical behaviours are often disrupted by hippocampal lesions, for example (p. 306) species-specific defence postures are impaired in lesioned rats and gerbils; maternal, sexual and social behaviours are also sometimes impaired (Table A27). But these impairments were generally interpreted in terms of spatial impairments, thus a lactating female was seen to execute a perfect “hover” but at a distance from her pups.

The present work was therefore designed to clarify the effects of hippocampal lesions in mice on tests of anxiety, and examine further examples of species-typical behaviours. The light–dark box [8], which measures the preference of rodents for a dark place, is a widely used anxiety test. When the present cohort of lesioned mice was tested in it, a complex pattern of behaviour emerged, with evidence for both increased and decreased anxiety (see Sections 3 Results, 4 Discussion). Notably, lesioned mice reacted very differently to the door separating the light and dark compartments. Their behaviour was therefore examined in a “tunnel maze” to assess whether they reacted differently to small openings in general. Other species-typical behaviours tested included digging, climbing and home cage sheltering behaviour. To confirm the reproducibility of earlier work and provide continuity, some tests of species-typical and other behaviours were repeated on this new cohort of mice; the methods and results for these tests are reported briefly for reasons of space.