Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice

Abstract

Many neuropsychiatric diseases are associated with cognitive rigidity linked to prefrontal dysfunction. For example, schizophrenia and Parkinson's disease are associated with performance deficits on the Wisconsin Card Sorting Test, which evaluates attentional set shifting. Although the genetic underpinnings of these disorders can be reproduced in mice, there are few models for testing the functional consequences. Here, we demonstrate that an analog of the Wisconsin Card Sorting Test, developed in marmosets and recently adapted to rats, is a behavioral model of prefrontal function in mice. Systematic analysis demonstrated that formation of the attentional set in mice is dependent on the number of problem sets. We found that mice, like rats and primates, exhibit both affective and attentional sets, and these functions are disrupted by neurotoxic damage to orbitofrontal and medial prefrontal cortical areas, respectively. These data are identical to studies in rats and similar to the deficits reported after prefrontal damage in a comparable task in marmosets. These results provide a behavioral model to assess prefrontal function in mice.

Figure 1.

Lesions demonstrate selective impairments in reversal learning and set-shifting ability. A, B, Distribution of lesioned areas. Cresyl violet staining was used to determine lesioned regions. The maximum extent of lesions is denoted by the lightest gray shading, and the minimum extent of lesions in all mice is shown by black shading. Representative affected areas, present in at least 50% of the subjects, are shown by medium gray. The figures represent n > 7 mice per group; no significant damage was observed in sections from the sham-lesion mice. Drawings were adapted from the atlas of Paxinos and Franklin (2001). C, D, Cresyl-violet-stained sections with OFC lesions. Arrows point to lesion area. E, GFAP immunoreactivity demonstrates gliosis at the OFC lesion site; the inset shows the location of the lesion in low power image. F, G, Cresyl-violet-stained sections of MFC lesions. In these images, bilateral lesions are shown by the arrows. H, GFAP immunoreactivity demonstrates gliosis at the MFC lesion site. Scale bar: C, F, 500 μm; D, G, 400 μm; E, H, 200 μm.

Figure 2.

Lesions selectively impair performance on reversal and set-shifting tasks. A, The number of trials to reach criterion is the same for training, whereas more trials are needed for the reversal learning (IDS IVrev) and for the ID–ED shift (EDS). The OFC-lesion group required more trials to complete the reversal task (IDS IVrev), and the MFC lesion required more trials for the ID–ED shift. *Significant difference between IDS IV and either IDS IVrev or EDS; ^#difference between control sham group and either the OFC- or MFC-lesioned group for the specific discrimination; ^&difference between the MFC- and OFC-lesioned groups for the specific discrimination. Significance is p < 0.05. Bars represent groups of n >7 mice per group. B, The numbers of errors recorded were similar between all groups during the learning phase. The OFC lesion group had significantly more errors than the sham group (^#p < 0.05) or the MFC group (^&p < 0.05) for the IDS IVrev task, whereas the MFC lesion group was similar to the sham group for the IDS IVrev. The MFC lesion group had significantly more errors on the EDS task, compared with the sham group (^#p < 0.05) or the OFC group (^&p < 0.05). OFC lesions did not affect performance on the EDS task.

Figure 3.

We systematically examined the effects of task number, presence and location of reversals, and inclusion of overtraining on set-shifting ability in mice (supplemental Table S2, available at www.jneurosci.org as supplemental material). To compare experimental groups, we calculated the ratio of trials needed for criterion for the EDS to those needed for the preceding IDS. In group 1, five separate tasks were insufficient to form as attentional set, as indicated by a ratio of ED/ID trials of 1. In groups 2 and 3, seven tasks were sufficient to form an attentional set. The main effect was observed with task number (F_(2,32) = 65.4, p < 0.0001). The presence or location of reversal discriminations or overtraining had no effect on set-shifting ability. Asterisks denote a significant different from group 1 (p < 0.04).