Research reportEffects of electrolytic lesions of the medial prefrontal cortex or its subfields on 4-arm baited, 8-arm radial maze, two-way active avoidance and conditioned fear tasks in the rat
Introduction
The rat medial prefrontal cortex (mPFC) has connections with diverse brain regions involved in perceptual, motor, cognitive, and autonomic-limbic functions 33, 53, 54, 63, 72. This diversity is paralleled by multiplicity of function ascribed to the mPFC. Thus, the mPFC has been implicated in various cognitive functions, such as rule learning and the ability to use and shift between behavioral strategies 2, 10, 36, 75, in working memory 17, 36, 68(although less agreement exists with regard to this function; e.g. 60, 76), in spatial learning (e.g. 37, 38, 39, 64), and in emotional processes, particularly in the aversive domain 23, 29, 30, 31, 32, 49, 50, 55.
The mPFC is a heterogeneous structure containing several cytoarchitectonically distinct subregions [71], which include along its dorsoventral axis the agranular medial cortex (AGm) (or Fr2 of [79]) (which has been suggested to include areas homologous to the primate premotor cortex, supplementary motor area, and frontal eye field 45, 46, 51, 52, 58, 70), dorsal anterior cingulate area (dACA), prelimbic cortex (PL), and infralimbic cortex (the latter is not considered by some writers to be part of the PFC, see [79]) 6, 12, 26, 28, 44, 61, 62, 70. These subregions differ in their pattern of connectivity 27, 32, 51, 52, 53, 54, 63, 67, 70, 74, thus implying functional distinction. However, the establishment of structure–function relationships for these subregions still lags behind the anatomical refinement.
Most of the evidence used to ascribe different functions to different mPFC subregions has several shortcomings: (1) Some structure–function relationships are based on comparisons of partial and complete mPFC lesions, which may confound selective involvement of the different subregions and a 'mass action'. For example, Dunnett [17]reported that lesions of the pregenual shoulder area (AGm and dACA) result in a delay-specific deficit in the delayed non-match to sample task, implicating these regions in working memory, while larger lesions, including in addition the more ventral regions of the mPFC, result in a non-delay-dependent deficit, suggesting that the more ventral regions of the mPFC are involved in the acquisition of the more general aspects of the task (see also 19, 34, 64, 68, 78). (2) Other conclusions are based on comparisons between different lesions in different experiments. For example, Brito et al.'s [3]conclusion that the PL cortex, rather than the shoulder area, is the critical site for spatial delayed alternation is not derived from a single study comparing the two lesions. (3) Finally, even studies using small mPFC lesions usually damage more than one mPFC subdivision (e.g. 8, 9, 19, 35, 76, but see [47]).
The present experiments sought to compare the behavioral functions of two mPFC subregions, dACA and PL. Anatomically, these regions differ in several sets of connections. The PL cortex has more extensive connections with autonomic and limbic brain regions compared with the dACA 32, 33, 43, 51, 53, 54, 63, 66, 67, 72, while the dACA has more extensive connections with second-order association areas, posterior parietal cortex, and premotor areas 26, 41, 42, 63, 70, 74. This pattern of connectivity suggests that the PL might be more involved in the autonomic and limbic functions ascribed to the mPFC, while the dACA might be more involved in the cognitive functions ascribed to the mPFC.
Behavioral results thus far give only partial support to this suggestion. Thus, manipulations of the ventral mPFC (including PL) but not the dorsal mPFC (including dACA) result in alterations of autonomic responses, particularly those evoked by stress (e.g. 29, 30, 31, 32, 41, 51, 54), although both regions appear to play a role in unconditioned and conditioned fear or anxiety 23, 47, 49, 50. There is a controversy with regard to the involvement of the shoulder area and PL cortex in the acquisition of spatial-delayed-alternation, a task involving both rule learning and working memory, and in which both regions have been implicated (shoulder area: 8, 18, 56; PL: 3, 4, 24, 68). Some studies which assessed working memory in operant chambers suggested that the shoulder area might be more involved in the working memory component of the task, while the PL cortex might be more involved in the more general aspects of the task 17, 58, 73, but others concluded that the shoulder area is involved in the acquisition of skill- and rule-based behavior [77]. In addition, lesions of the ventral and dorsal mPFC (including PL and dACA, respectively) were found to induce similar effects on behavioral flexibility [9].
The present study tested the effects of electrolytic lesions in two mPFC subregions, the dACA and PL, on 4-arm baited, 4-arm unbaited, 8-arm radial maze task and its reversal (Experiment 1), two-way active avoidance (Experiment 2) and conditioned emotional response (CER; Experiment 3), as well as the effects of a larger mPFC lesion, which included both subregions, on these tasks (Experiments 4, 5, and 6, respectively). We have chosen the avoidance and CER tasks to test the involvement of the mPFC and its subregions in emotional processes 7, 15, 25, and the radial maze task to test their involvement in working and reference memory. We added a reversal stage to the radial maze task in order to obtain a better assessment of reference memory, since a rat with an impaired reference memory should be less affected by reversal.
Section snippets
Subjects
Male Wistar rats (Tel-Aviv University Medical School, Israel) approximately 4 months old, weighing 300–420 g, were housed in pairs under reversed cycle lighting (lights on 1900–0700). Animals were maintained on ad lib food and water except for a week prior to and during the radial maze and CER tasks (see below).
Surgery
Rats were anesthetized with an i.p. injection of Equithesin (3.0 ml/kg). They were placed in a stereotaxic frame and an incision was made into the scalp to expose the skull. The vertical
Anatomical
Representative reconstruction of the dACA and PL lesions is presented in Plate I, columns A and B, respectively. The dACA lesions obtained were triangular in cross-section and elongated in the anteroposterior axis. In most animals the lesion extended A–P 4.2–2.2 mm anterior to bregma. Restricted damage to the most dorsal aspect of Cg3 (PL) and the most medial aspect of Fr2 (AGm) was detected in most of the rats. The PL lesions obtained were circular in cross-section and elongated in the
Discussion
Rats with large or small lesions of the mPFC learned the location of the 4 baited arms in the radial maze task similarly to sham rats, as reflected in similar acquisition curves of the RME and W-RME. dACA and mPFC lesions slowed down the acquisition of the 4-arm baited, 8-arm radial maze task, as a result of a slower rate of reduction in WME. However, impaired performance of the dACA and mPFC rats on the working memory component of the task was evident at the initial stages of training, whereas
Acknowledgements
This research was supported by grants from the Israel Academy of Sciences and Humanities, the Ministry of Science and The Arts, Israel and the Commission of the European Community, and the Josef Buchmann Doctoral Fellowship Fund to D.J.
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