α7 nicotinic ACh receptor‐deficient mice exhibit sustained attention impairments that are reversed by β2 nicotinic ACh receptor activation

Abstract

BACKGROUND AND PURPOSEDisruptions of executive function, including attentional deficits, are a hallmark of a number of diseases. ACh in the prefrontal cortex regulates attentive behaviour; however, the role of α7 nicotinic ACh receptor (α7nAChR) in attention is contentious. EXPERIMENTAL APPROACHIn order to probe attention, we trained both wild-type and α7nAChR knockout mice on a touch screen-based five-choice serial reaction time task (5-CSRT). Following training procedures, we then tested sustained attention using a probe trial experiment. To further differentiate the role of specific nicotinic receptors in attention, we then tested the effects of both α7nAChR and β2nAChR agonists on the performance of both wild-type and knockout mice on the 5-CSRT task. KEY RESULTSAt low doses, α7nAChR agonists improved attentional performance of wild-type mice, while high doses had deleterious effects on attention. α7nAChR knockout mice displayed deficits in sustained attention that were not ameliorated by α7nAChR agonists. However, these deficits were completely reversed by the administration of a β2nAChR agonist. Furthermore, administration of a β2nAChR agonist in α7nAChR knockout mice elicited similar biochemical response in the prefrontal cortex as the administration of α7nAChR agonists in wild-type mice. CONCLUSIONS AND IMPLICATIONSOur experiments reveal an intricate relationship between distinct nicotinic receptors to regulate attentional performance and provide the basis for targeting β2nAChRs pharmacologically to decrease attentional deficits due to a dysfunction in α7nAChRs.

Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention

“…Interference with the cholinergic system can produce fluctuations in attentive engagement in 5CSRTT 45,46 . Analysis of attention performance in distinct temporal phases of 5CSRTT sessions showed that inhibiting cholinergic BF-to-mPFC projections reduced accuracy of responding only during the first half of the session (early trials 0–50), but not the second half of the session (late trials 51–100) (Fig.…”

Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention

“…Interference with the cholinergic system can produce fluctuations in attentive engagement in 5CSRTT 42,43 . Analysis of attention performance in distinct temporal phases of 5CSRTT sessions showed that inhibiting cholinergic BF-to-mPFC projections reduced accuracy of responding only during the first half of the session (early trials 0-50), but not the second half of the session (late trials 51-100) (Fig 5H).…”

MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment

“…We did not formally calculate power analysis a priori. Typical experiments using the Bussey-Saksida touchscreen technology use samples sizes between 7 and 13 mice per group (Beraldo et al, 2015; Kolisnyk et al, 2015; Kolisnyk et al, 2013; Lim et al, 2019; Romberg et al, 2013b; Romberg et al, 2011). Based on these previous studies, and depending on cohort availability, we assigned a minimum of 10 animals per genotype, sex and site, anticipating some mortality.…”