Too little and too much: medial prefrontal functional inhibition impairs early acquisition of operant reversal learning, whereas medial prefrontal disinhibition impairs established serial-reversal performance in rats

Schizophrenia has been linked to hypofrontality (reduced prefrontal activation) and neural disinhibition (reduced GABAergic inhibition) within the dorsolateral prefrontal cortex (dlPFC), as well as reversal learning deficits. Interestingly, whilst reversal learning has been strongly linked to the orbitofrontal cortex, research suggests that the primate dlPFC – or its rodent analogue, the medial PFC (mPFC) – is less important for this process. Nevertheless, we hypothesized that the mPFC may be required for reversal learning if the reversal is particularly demanding. Furthermore, even if the mPFC is not required, mPFC disinhibition may impair reversals, because it may disrupt processing in mPFC projection sites. To test this, we induced mPFC functional inhibition and disinhibition in rats, using microinfusions of the GABA-A receptor agonist muscimol or antagonist picrotoxin, respectively, and examined the impact on early and serial reversals on a food-reinforced two-lever discrimination task. Using classical performance measures and Bayesian trial-by-trial strategy analysis, we found that mPFC functional inhibition impaired early, but not serial, reversals by increasing perseveration and impairing exploratory (lose-shift) behavior. In contrast, disinhibition impaired serial reversals, which was associated with reduction in both exploratory (lose-shift) and exploitative (win-stay) behavior. These findings suggest that mPFC hypoactivation and disinhibition disrupt distinct aspects of reversal learning by different mechanisms.