CELL-TYPE-SPECIFIC Α7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATION OF GABAERGIC INTERNEURONS UNDERLYING COGNITIVE FLEXIBILITY

Organisms continuously adapt their behavior to changing environmental demands, a capacity that relies on cognitive flexibility, the ability to shift between thoughts and actions. Although the mechanisms underlying this process remain unclear, the prefrontal cortex (PFC) is known to play a central role in cognitive flexibility, which is frequently impaired in psychiatric disorders. Cholinergic projections from the basal forebrain modulate PFC activity through acetylcholine receptors, including the α7 nicotinic acetylcholine receptor (nAChR), a receptor implicated in neuropsychiatric pathophysiology. In this study, we investigated the specific contribution of α7 nAChRs expressed in Neuron-Derived Neurotrophic Factor (NDNF)-expressing interneurons, key inhibitory neurons in cortical layer 1, and in parvalbumin (PV)-expressing interneurons of layers 2/3 in the PFC during cognitive processing. Using NDNF-Cre α7^flox and PV-Cre α7^flox mice, we selectively deleted α7 nAChRs in these interneuron populations and assessed a battery of cognitive behaviors, including cognitive flexibility. Mutant mice exhibited significant impairments during rule-shift tasks, requiring more trials to reach criterion and committing more errors than control littermates, indicating reduced cognitive flexibility. Two-photon calcium imaging in awake, behaving mice combined with pharmacological manipulations revealed differential regulation of distinct interneuron types by α7 nAChRs. Together, these findings demonstrate that α7 nAChRs critically modulate cortical inhibitory circuits that support cognitive control, providing a potential mechanistic link between cholinergic dysfunction and cognitive deficits in psychiatric disorders and highlighting novel avenues for therapeutic intervention.