Effects of chronic intermittent ethanol exposure on orbitofrontal and medial prefrontal cortex-dependent behaviors in mice

Abstract

In humans, stroke or trauma-induced damage to the orbitofrontal cortex (OFC) or medial prefrontal cortex (mPFC) results in impaired cognitive flexibility. Alcoholics also exhibit similar deficits in cognitive flexibility, suggesting that the OFC and mPFC are susceptible to alcohol-induced dysfunction. The present experiments investigated this issue using an attention set-shifting assay in ethanol dependent adult male C57BL/6J mice. Ethanol dependence was induced by exposing mice to repeated cycles of chronic intermittent ethanol (CIE) vapor inhalation. Behavioral testing was conducted 72 hours or 10 days following CIE exposure to determine whether ethanol-induced changes in OFC-dependent (reversal learning) and mPFC-dependent (set-shifting) behaviors are long lasting. During early ethanol abstinence (72 hrs), CIE mice showed reduced reversal learning performance as compared to controls. Reversal learning deficits were revealed as greater number of trials to criterion, more errors made, and a greater difficulty in performing a reversal learning task relative to baseline performance. Furthermore, the magnitude of the impairment was greater during reversal of a simple discrimination rather than reversal of an intra-dimensional shift. Reversal learning deficits were no longer present when mice were tested 10 days after CIE exposure, suggesting that ethanol-induced changes in OFC function can recover. Unexpectedly, performance on the set-shifting task was not impaired during abstinence from ethanol. These data suggest reversal learning, but not attention set-shifting, is transiently disrupted during short-term abstinence from CIE. Given that reversal learning requires an intact OFC, these findings support the idea that the OFC may be vulnerable to the cognitive impairing actions of ethanol.

Figure 1. Experimental design for the reversal learning and set-shifting experiments

A) Experiment 1 design B) Experiment 2 design. In this and all subsequent Figures, abbreviations denote type of task. SD = simple discrimination, CD = compound discrimination, ID = intradimensional shift, Rev = reversal learning, ED = extradimensional shift.

Figure 2. Reversal learning and set-shifting in CIE mice

Number of trials required to reach criterion (A, D), errors committed (B, E) and latency to obtain the bait (C, F) were measured on discrimination trials before CIE exposure (left panels) and 72 hrs following the last CIE exposure (right panels). Data in the left panels are collapsed across Treatment groups (N = 20/bar). Data in the right panels represent CIE (N = 11) and control (N = 9) mice. All bars represent mean ± SEM. # = differs from SD or previous ID.

Figure 3. Reversal learning is impaired during early but not protracted ethanol abstinence

Number of trials required to reach criterion (A, D), errors committed (B, E) and latency to obtain the bait (C, F) were measured on discrimination trials 72 hrs (left panels) and 10 days (right panels) following the last CIE exposure (72 hrs CIE n = 10, control n = 9, 10 days CIE n = 16, control n = 10). All bars represent mean ± SEM. * = differs from control; # = differs from SD2.

Figure 4. CIE-induced cognitive impairment during reversal learning is dependent on the type of reversal learning task utilized

Percent change from SD (baseline) for the number of trials required to reach criterion (A), errors committed (B) and latency to obtain the bait (C) were compared between Experiment 1 (RevID4) and Experiment 2 (RevSD) protocols. All mice were tested at 72 hours following the last CIE exposure. Scores were taken from Table 4. All bars represent mean ± SEM. * = differs from control.