The encoding of cognitive flexibility by the prefrontal cortex and its modulation by dopamine- and clinically-relevant genetic variants

Cognitive flexibility, defined as the ability to switch a specific response in a quick manner depending on changes in the environment, is an executive function critically altered in psychiatric disorders such as schizophrenia (Nęcka and Orzechowski, 2004; Collins and Koechlin, 2012; Lunt et al., 2012). The prefrontal cortex (PFC) is a major hub involved in the mediation of cognitive flexibility. This brain area receives consistent dopaminergic inputs (Carr et al., 1999; Björklund and Dunnett, 2007; Puig, Antzoulatos and Miller, 2014), indeed, dopamine signaling within the PFC is suggested to be implicated in the causes and treatment responses of cognitive deficits evident in schizophrenia. However, how the PFC might code different components of cognitive flexibility at the single-cell level and how this might be modulated by dopamine- and clinically-relevant functional genetic variants is still not clear. Here, I addressed this by using in vivo electrophysiology recordings in the PFC of wild-type and clinically-relevant mouse mutants with genetic variants altering D2 receptors while performing a cognitive flexibility task with high clinical translational relevance. In particular, while mice were performing a recently validated automated Intra-/Extra-Dimensional Attentional Set-Shifting task for mice (Scheggia et al., 2014, 2018), I recorded PFC activity with in vivo oximetry and then single-unit extracellular electrophysiology. I used wild-type mice and three different genetically modified mice with the alteration of the dopamine/D2 signaling: Dysbindin +/- mice, with overexpression of cortical D2 receptors, D2L +/- mice, with an unbalance of D2 isoforms and the combination of these genetic variants (dys+/-D2L+/-). The main finding I found was that, while WT animals show an increase in both oxygen consumption and neuronal activity, particularly during the extra-dimensional shift (EDS) following correct response, the same effect was altered in dys+/- mice. Unbalancing the ratio of the two D2 isoforms, there was an alteration of the neural activity during serial reversal learning. The concurrent alteration of both genes differentially impacted mice's behavior together with their respective cortical activity across the different stages. These findings provide specific associations between schizophrenia-relevant genetic variants related to dopamine/D2 signaling and PFC neuronal activity related to cognitive flexibility. This has implications in the understanding of cognitive flexibility alterations present in psychiatric disorders and in the possible development of genetic-based personalized approaches for these deficits.