DISSECTING THE INVOLVEMENT OF PREFRONTAL Α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN INHIBITORY CONTROL ACROSS PHYSIOLOGICAL AND PATHOLOGICAL STATES

Alterations in α7 nicotinic acetylcholine receptors (α7*nAChRs) and their genetic regulation have been implicated in several neuropsychiatric disorders, including schizophrenia and Alzheimer’s disease. Preclinical studies indicate that α7nAChR ligands can improve executive functions, which are commonly impaired across these conditions. However, these findings have not yet translated into effective clinical treatments.
To address this translational gap, we developed an integrative approach combining transgenic rat models, viral vector-mediated region-specific gene expression, touchscreen-based behavioral paradigms, and pharmacological manipulations to investigate the role of α7*nAChRs with anatomical resolution.
Our results show that rats lacking the α7 subunit (α7KO) display a general impairment in inhibitory control, as assessed using the continuous performance task and the differential reinforcement of low rates of responding task. These deficits appear to be independent of alterations in attention, learning, or motivation.
Beyond these findings, our work aims to elucidate the contribution of α7*nAChRs to the development of cognitive dysfunctions associated with neuropsychiatric disorders, with a particular focus on their interaction with amyloid-beta in a rat model of amyloid-beta pathology. In this context, we show that overexpression of a mutated form of the amyloid-beta precursor protein within a specific subregion of the prefrontal cortex induces cognitive alterations that depend on the presence of α7nAChRs.
Altogether, this study highlights a critical role for α7nAChRs in response inhibition and supports the use of this experimental framework as a relevant platform for the preclinical screening of novel α7*nAChR-targeting compounds with therapeutic potential.