More Is Less: A Disinhibited Prefrontal Cortex Impairs Cognitive Flexibility

NVHL rats can learn the task. A, B, Number of trials (A) and number of response errors (B) for NVHL (red) and sham (black) rats during the initial training sessions in which only the two forced-choice trials were presented. Delays between task events were increased across trials to the values used in the full task during recording sessions. There were no differences in the number of trials and response errors between groups (ANOVA, p > 0.05, n = 11). C, Illustration of histologically verified damage to the ventral hippocampus in adult NVHL rats indicated on a standard atlas (Paxinos and Watson, 2005). Gray and dark regions show the largest and smallest extent, respectively, of damage across rats.

Loss of field-potential modulation in NVHL rats during the task. A, Histologically identified electrode tracks in the medial PFC for control and NVHL rats. Prelimbic (PL) and infralimbic (IL) cortical areas are labeled according to a standard atlas (Paxinos and Watson, 2005). B, Task-averaged time-frequency spectrograms of field potentials reveal reduced power for NVHL rats (bottom; n = 6) and sham controls (top; n = 5). Data are aligned to odor port entry, normalized to the 0.5 s interval before port entry, and include only field potentials recorded during correct trials. C, Loss of field potential (FP) power in NVHL rats is observed across several frequency bands. Summed field potential power within conventional frequency bands for NVHL (red) and control (gray) rats shows reduced modulation in NVHL rats during odor presentation (yellow boxes, p < 0.01 by Bonferroni corrected t test indicated by *) for all frequency bands <30 Hz. D, Field potential power spectra for NVHL (red) and control (gray) rats during baseline and odor presentation epochs, revealing less oscillation amplitude in NVHL rats in gamma and other frequency ranges (p < 0.05 by jackknifed U-statistic indicated by a blue line below the plot). Shaded regions represent mean ± SEM. n.s., Not significant.

Single-unit responses during the task. A, Raster plot and perievent time histogram for a putative pyramidal neuron recorded from a control rat performing the decision-making task. Colored bars indicate odor cue (green, free choice; red, forced right; blue, forced left) and triangles indicate reward delivery (red, right; blue, left). B, Bar plots showing the percentage of units from control (black; n = 86) and NVHL (red; n = 159) rats responding with significant increases of firing during each region of interest labeled above the bars. †Differences between the number of units, computed by χ². C, Group averages of raw firing rates (top) and z scores (bottom) for PFC single units that showed a significant increase in activity during task epochs for NVHL (dashed red line) and control (solid black line) rats. Data for each epoch are aligned to the task event indicated by labels above vertical lines. Baseline firing was not different between the two groups; however, NVHL rats showed increased firing during the task. *p < 0.05 by t test of mean cell firing during regions of interest marked by blue bars above plots. Lines indicate mean and shaded regions represent ±SEM.

Bar plot showing the proportion of units that had a dependence on reward size for sham (black) and NVHL (gray) rats over multiple task epochs. Reward dependence was assessed by computing firing in each epoch for large and small reward trials to the preferred response direction for each unit, and testing for significant differences of firing in these conditions using the Wilcoxon rank sum test. *p < 0.05 by χ² test between groups for each epoch.

Behavioral deficits in NVHL rats. A, Plot of group-averaged response (resp.) choices during sequential free-choice trials within behavioral blocks, showing that both groups of rats develop a bias against the well giving small rewards as blocks progress, but NVHL rats (gray, n = 6) showed less bias than control rats (black, n = 5). B, Bar plot of response errors on forced-choice trials showing that rats made more response errors on forced trials for small rewards and that NVHL rats made more response errors than controls. C, Bar plot of reaction times showing that rats had faster reaction times for big rewards than small rewards, and NVHL rats had faster reaction times than controls for both reward sizes. D, Bar plot of premature exits from the odor port showing that NVHL rats had a nonstatistically significant trend to make more premature exits from the odor port. E, Bar plot of mean change in responses away from the discounted reward well on the first five free-choice trials in each block compared with the preblock bias, showing response perseveration in NVHL rats on the second block compared with controls. For all plots, significance at the 95% level by main effects of two-way ANOVA (†), Tukey–Kramer post hoc test (*) and t test (**) are indicated. Error bars indicate ±SEM. F, Changes in field-potential power during odor presentation correlate with performance in the task. Error rate during forced-choice trails plotted against average power during odor presentation normalized by the preodor value for the 1–30 Hz frequency band in control rats. The line was generated by linear regression of data points. n.s., Not significant.