Unravelling the role of prefrontal α7 nicotinic acetylcholine receptors in inhibitory control in physiological and pathological contexts: A behavioral investigation using touchscreen technology

Dysfunctional α7 nicotinic acetylcholine receptors (α7*nAChRs) and their genetic regulation have been associated with several neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). Preclinical studies revealed that α7*nAChR ligands can improve executive function, commonly impaired across neuropsychiatric disorders. Yet, a translational gap prevents these findings from resulting into clinically effective treatments. To tackle this translational gap, we combine approaches such as transgenic rats, viral vector-mediated local gene expression, touchscreen-based behavioral assays, and pharmacological manipulations, to investigatethe role of these receptors with region-specific resolution. Our findings show that knockout rats for the α7 subunit gene (α7KO) present a general deficit in inhibitory control as observed in the continuous performance task and the differential reinforcement of low-rates of responding task, which seems unrelated to deficits in attention, learning or motivation, and unlikely to be due to compensatory alterations in non-⍺7 nAChR subunits’ expression. We further aim at unravelling the importance of α7*nAChRs expressed in the infralimbic cortex and in the anterior cingulate cortex in the modulation of cognition by re-expressing these receptors specifically in these regions in α7KO rats. Finally, we aim at identifying the contribution of α7*nAChRs to the development of cognitive deficits in the context of neuropsychiatric disorders, and, in particular, the putative interaction between these receptors and the amyloid beta peptide in a rat model of AD. So far, our approach has revealed a crucial role of α7*nAChRs in response inhibition and represents a promising tool to screen new α7*nAChR ligands for therapeutical purposes.