Resistance of experientially-induced changes in murine plus-maze behaviour to altered retest conditions

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Abstract

Prior exposure to the elevated plus-maze results in profound behavioural alterations in rats and mice, with 24 h retest profiles indicative of fear sensitization. The present study was designed to examine the influence of retest cues on this phenomenon in male DBA/2 mice. Results confirmed the potent influence of prior maze experience on subsequent behavioural patterns, and showed that this was not affected by manipulations of extra-maze cues (90° re-orientation of the maze or use of a different laboratory) on Trial 2. Data are discussed in relation to experientially-induced shifts in behavioural strategy and the apparent involvement of simple proximal cues (probably thigmotactic) in this enduring and adaptive form of spatial learning.

Introduction

The elevated plus-maze is currently one of the most widely-used animal models of anxiety, having been employed by over 100 different research laboratories in the past 5 years [20]. It is an example of what Lister [26]described as an ethological model, and has been extensively validated for use with both rats [35]and mice [25]. The conventional indices of anxiety in this test, % open arm entries and % open arm time, are exquisitely sensitive to agents thought to act via the GABAA receptor complex (i.e. benzodiazepines, barbiturates, ethanol, and neurosteroids) 20, 36. Although the test is generally less sensitive to novel anxiolytics, such as buspirone, it has been argued that such problems may at least partially be overcome by extending the measures to include a range of specific behavioural acts and postures related to risk assessment 1, 7, 12, 19, 28, 36, 38, 45.

An intriguing and potentially important aspect of the plus-maze paradigm is the finding that a single prior undrugged exposure reduces or abolishes the subsequent anxiolytic efficacy of chlordiazepoxide and diazepam 13, 15, 25, 40, 41. This effect, initially described as `one-trial tolerance', critically depends upon initial experience of the open arms and occurs with inter-trial intervals ranging between 24 h and 2 weeks 13, 15, 25, 39. The proposal that the nature of the anxiety state engendered on reexposure may qualitatively differ to that experienced on initial testing [40]has been supported by the finding that the primary anxiety indices in the two trials load on separate factors 12, 18, 21. In turn, these observations have prompted speculation that, during initial exposure, animals acquire a phobic avoidance of the open arms thereby explaining the lack of benzodiazepine response in maze-experienced animals 16, 18. The finding that rats and mice display rapid spatial learning during initial exposure to the maze 39, 44, and that this learning readily transfers between trials 2, 8, 12, 19, 22, 24, 40, 41, 46, is consistent with this proposal. Thus, open arm exploration decreases (closed arm exploration increases) from the first to the last minute of initial exposure, with the pattern observed by the end of that session generally maintained on retest. In this context, it is significant that the plasma corticosterone response to the maze does not habituate between trials [17].

While the neurobiological mechanisms underlying such within- and between-trials behavioural changes are at present unknown [39], the possibility that the Trial 2 profile constitutes a different type of anxiety prompts questions regarding the environmental cues involved in plus-maze learning. Previous research on rats has suggested that an experientially-induced loss of benzodiazepine efficacy is observed even when retesting occurs on a maze constructed of different materials [15]. However, in a version of the murine plus-maze adapted for memory research, a change in test laboratory (but not maze orientation) on Trial 2 has been reported to eliminate the reduction in open arm transfer latencies normally observed when testing and retesting are conducted in the same laboratory [29]. In view of these findings, and evidence regarding the variable importance of intra- and extra-maze cues in other spatial learning tasks 30, 31, 33, 42, the present study assessed whether alterations in maze orientation or laboratory environment would influence experientially-induced changes in the plus-maze profiles of DBA/2 mice.

Section snippets

Animals

Subjects were 10–11-week-old male DBA/2 mice (Biomedical Services, University of Leeds), housed in groups of 10–12 per cage (45×28×13 cm3) for at least 4 weeks prior to testing. They were maintained under 12 h reversed lighting conditions (lights off at 07:00 h) in a temperature (21±1°C) and humidity (52±2%) controlled environment. Food and water were freely available with the exception of the brief test sessions.

Apparatus

The plus-maze was a modification of that validated for NIH Swiss mice by Lister

Results

Results are summarized in Fig. 1Fig. 2, and Table 1. ANOVA summary statistics are presented in Table 2.

Discussion

Factor analytic studies have shown that the behaviour of rodents in the elevated plus-maze test is more complex than previously assumed. Thus, while early work suggested that profiles could be accommodated by two factors, anxiety and activity 14, 25, studies which have recorded specific behavioural acts and postures (in addition to conventional open arm avoidance parameters) have identified mutliple behavioural dimensions 7, 12, 28. More specifically, the behaviour pattern of naı̈ve DBA/2 mice

Acknowledgements

The authors thank Dr Robert Adamec for stimulating the present study. NJTJ was supported by a University of Leeds Research Scholarship.

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