Research report
Medial prefrontal and neostriatal lesions disrupt performance in an operant delayed alternation task in rats

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Abstract

An operant version of the classical delayed alternation task is presented and applied to evaluate the effects of bilateral prefrontal and striatal lesions in rats. Retractable levers in a conventional operant chamber control discrete trial opportunities for making sequential choice responses to the two sides, and the rats are required to maintain repeated nose poke responses to a central panel during the delay interval, which is randomly varied. The operant task provides measures of the speed and accuracy of response alternation and side bias; analysis at different delay intervals provides an index of the memory demands of accurate performance; and analysis of accuracy depending on the response on preceding trials provides measures of proactive interference and perseveration. Following pretraining in the task contingencies, both striatal and prefrontal lesions induced profound deficits in task accuracy, with no change in side bias and only small changes in movement times. The deficit in the prefrontal lesion group recovered more rapidly, neither group showed any change in sensitivity to proactive interference, while the rats with striatal lesions alone exhibited an increased tendency to perseverate incorrect responses on either side. We conclude that the operant delayed alternation task should assist analysis of fronto-striatal function in rats as well as be useful for the analysis of strategies for fronto-striatal repair.

Introduction

Ever since Jacobsen’s classic studies in the 1930s [35], [36], spatial delayed response and spatial delayed alternation tasks have provided classic measures of prefrontal cortex dysfunction in monkeys [3], [6], [14], [31], [37], [42], [43] and in rats [10], [25], [38], [39], [62], [67], [68]. Based on the anatomical association of prefrontal cortex and anterior striatum, Rosvold first proposed that the neostriatum is a major subcortical nucleus in a prefrontal circuit for the control of cortical function, and subsequent studies have demonstrated that striatal lesions in rats and monkeys can mimic many of the deficits observed after prefrontal lesions [11], [12], [14], [55], [56], [57], [58]. This system is now conceptualised as one of the major parallel cortical-basal ganglia loops within the forebrain comprising a ‘prefrontal’ circuit involved in processing essential cognitive functions associated with the prefrontal cortex [1], [2]. Consequently, delayed alternation tasks have been among the most popular to assess cognitive aspects of striatal function [48] and a series of studies have confirmed deficits on this classic prefrontal test after lesions in the medial striatum of rats [13], [34], [44], [47], [49], [52], [67] and other species [3], [14], [47].

Previous studies of delayed alternation function in rats have primarily been based on training in various types of maze apparatus, including T-maze, Y-maze, Grice box and swimming pools. Such tests are easy to establish but training is labour intensive and does not facilitate the systematic collection of other aspects of performance (such as the speed of responding) or a systematic variation of delay intervals. These latter functions are more readily obtained in operant tasks. However, although both free operant schedules [23], [40], [60] and other discrete trial operant tasks [4], [15], [16], [41] have been used to asses the effects of striatal lesions, operant versions of delayed alternation tasks have been less successful [44]. Specifically, in this latter study, Mogensen and colleagues employed an operant chamber with two fixed keys; with the time window for making an alternation response signalled by flashing lights. Under these circumstances both striatal and intact rats learned over 10–20 sessions to alternate their responses during the signalled trials in the operant task, primarily by adopting strong positional mediating responses, even though the same lesioned animals exhibited marked deficits when trained to alternate in a conventional T-maze [44].

In previous studies to develop operant spatial delayed matching and non-matching to position tasks (DMTP and DNMTP, respectively) in rats, we have used retractable levers in an operant chamber to designate discrete trials when an animal may make choice responses to one of two levers located on either side of a central food well. We reduced the rats’ opportunities for making simple lateralised positional mediating responses by requiring them to press the central panel (covering the food well) repeatedly during the delay interval [19], [21]. By making presentation of the levers contingent upon a panel press response on a variable interval schedule, a stable high rate of responding at the central panel is assured throughout the interval [21], [29]. This task has been widely used to evaluate the effects of cortical and subcortical lesions, various pharmacological treatments and ageing on memory and other aspects of cognitive function [8], [9], [19], [20], [22], [27], [50], [59], [61]. However, whereas lesions or drug infusions into medial prefrontal cortex of rats produce reliable impairments in DMTP/DNMTP [5], [7], [20], [26], [33], [54], striatal lesions produce rather modest deficits that recover rapidly [16], [17].

This study was therefore designed to adapt the DNMTP task from a delayed non-matching contingency (in which a response to a single sample lever is followed by a choice response between two levers on each trial, akin to the pair-trial alternation protocol in a T-maze [53]) to an ‘operant delayed alternation’ task, requiring alternation between two choice levers on successive trials in the operant chamber, akin to the classic delayed alternation contingency employed in rodent maze tasks.

Section snippets

Subjects

The subjects were 30 young adult male rats of the hooded Lister strain (Charles River, UK). They were housed in groups of 4–5 rats per cage under a reverse 12 h/12 h light/dark cycle (lights off at 09:30 h). During behavioural testing, the animals were maintained on a food deprivation regime, fed 14–17 g lab chow per day so as to maintain ≈90% of free-feeding body weight. All experimental testing was conducted during the dark phase of the cycle, with food given 1–4 h after the completion of

Histology

Photomicrographs of representative control, prefrontal and striatal lesions are shown in Fig. 2. The prefrontal lesions were effective in removing the rostral parts of the medial wall of the prefrontal and anterior cingulate cortex (Fig. 2B,C). In the majority of cases, the floor of the lesion extended ventrally to the dorsal surface of the olfactory bulb, although in the smallest lesions the ventral-most part of the medial wall neocortex was spared (Fig. 2C and 3). In no case did the lesion

Discussion

In this study we use a novel operant version of the classical delayed alternation task for rats, which we have validated by comparing the effects of medial prefrontal and anteromedial striatal lesions.

Conclusion

In summary, an operant delayed alternation task is introduced that allows collection and analysis not only of simple measures of choice accuracy, but also parameters of bias, speed and rates of responding, short-term memory and forgetting within a trial, and proactive interference and perseveration of incorrect responses between trials. Execution of the delayed alternation contingency is disrupted both by prefrontal and by striatal lesions, as predicted by the anatomical connectivity of these

Acknowledgements

This research was supported by grants from the Medical Research Council.

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