Stage-dependent Effects of "too Little and Too Much" Medial Prefrontal Activity on Reversal Learning in Rats: Functional Inhibition Impairs Early, Whereas Neural Disinhibition Impairs Late Reversals.

Schizophrenia is associated with prefrontal cortex dysfunction, including neural disinhibition (reduced GABAergic inhibition) and hypoactivation ('hypofrontality'), alongside impaired reversal learning. However, evidence implicating prefrontal regions, including the rodent medial PFC (mPFC), in reversal learning is mixed. mPFC involvement may scale with demand for mPFC-dependent attention and cognitive control to overcome prepotent responses and to learn that reward contingencies can reverse, which is highest during early reversals. We therefore hypothesized that (1) the mPFC is required for early reversal learning but less important when reversal proficiency is high during late reversals. Furthermore, mPFC disinhibition may impair cognitive performance by causing circuit-level disruption outside the mPFC. Therefore, we hypothesized that (2) even when the mPFC is not required, mPFC disinhibition may impair reversal performance. To test hypotheses (1) and (2), we first examined the effect of mPFC functional inhibition and disinhibition, by microinfusion of the GABA-A receptor agonist muscimol and antagonist picrotoxin, on early reversals (reversals 1-3) versus late reversals (reversal 5 onwards) on a 2-lever discrimination task in adult male rats. mPFC functional inhibition by muscimol impaired only early reversals, increasing perseveration and impairing lose-shift behavior at reversal 2. In contrast, mPFC disinhibition by picrotoxin impaired late reversals, reducing lose-shift and win-stay behavior. Using chemogenetic mPFC disinhibition (hM4Di-mediated inhibition of GABAergic neurons), we further tested hypothesis (2). Similar to mPFC picrotoxin, chemogenetic mPFC disinhibition impaired late reversals, primarily disrupting win-stay behavior. Our findings suggest that reduced and disinhibited mPFC activity impair distinct aspects of reversal learning.Significance statement Schizophrenia is associated with reduced activation ("hypofrontality") and neural disinhibition (reduced GABAergic inhibition) within the prefrontal cortex (PFC). However, 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 lose-shift behavior, whereas prefrontal disinhibition disrupted late reversals, impairing both lose-shift and win-stay behavior. Our findings suggest that reduced activation and disinhibition of PFC disrupt distinct aspects of reversal learning, by distinct mechanisms.