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 is associated with reduced activation ( hypofrontality) and neural disinhibition (reduced GABAergic inhibition) in the dorsolateral prefrontal cortex (dlPFC), as well as reversal learning deficits. Whilst reversal learning has been strongly linked to the orbitofrontal cortex, its dependence on the primate dlPFC - and its rodent analogue, the medial PFC (mPFC) - is less clear. Nevertheless, we hypothesized that the mPFC may be required for reversal learning if the reversal is 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 these hypotheses, we combined bi-directional manipulations of mPFC GABAergic inhibition, using intracerebral drug microinfusion and chemogenetic/DREADD methods, with reversal testing on a food-reinforced two-lever discrimination task in rats. First, we induced mPFC functional inhibition and disinhibition, by microinfusion of the GABA-A receptor agonist muscimol or antagonist picrotoxin, respectively, and examined the impact on early reversals (reversals 1-3) and well-established serial reversals (reversal 5 onwards). Using classical performance measures and Bayesian trial-by-trial strategy analysis, we found that mPFC muscimol impaired early, but not serial, reversals, increasing perseveration and impairing exploratory (lose-shift) behavior at reversal 2. In contrast, mPFC picrotoxin impaired serial reversals, reducing exploratory (lose-shift) and exploitative (win-stay) behavior. Second, to inhibit mPFC GABAergic neurons, we expressed the inhibitory DREADD hM4Di in these neurons; chemogenetic mPFC disinhibition by activation of hM4Di also impaired serial reversal learning, primarily disrupting exploitation. Our findings suggest that mPFC hypoactivation and disinhibition disrupt distinct aspects of reversal learning by different mechanisms. Significance statementSchizophrenia is associated with reduced activation ("hypofrontality") and neural disinhibition (reduced GABAergic inhibition) within the prefrontal cortex (PFC). Yet, it is not clear if and how these distinct aspects of prefrontal dysfunction contribute to impaired reversal learning, a key feature of the cognitive inflexibility characterizing schizophrenia. Here, we combined bi-directional manipulations of prefrontal GABAergic inhibition with testing of reversal learning in rats. Increasing prefrontal functional inhibition (i.e., reducing prefrontal activation) selectively impaired early reversals, enhancing perseveration and reducing exploratory (lose-shift) behavior, whereas prefrontal disinhibition disrupted serial reversals, impairing both exploration and exploitation. Our findings suggest that reduced activation and disinhibition of PFC disrupt distinct aspects of reversal learning, by distinct mechanisms.