The retrosplenial cortex (RSC) and the hippocampus (HP) are critical brain regions involved in memory processing and are among the first to deteriorate during the early stages of Alzheimer’s disease. Alpha-7 nicotinic acetylcholine receptors (α7nAChRs) play a central role in synaptic plasticity mechanisms that support memory functions. Given the dense bidirectional connectivity between the RSC and HP, investigating how α7nAChRs modulate their interaction offers a promising avenue to elucidate the circuit-level mechanisms underlying memory. In previous work, we showed that blocking α7nAChRs in the RSC of rats with methyllycaconitine (MLA) before inhibitory avoidance (IA) training enhanced memory expression 24 hours later. Here, we extend these findings by demonstrating that PNU-120596 (PNU), an α7nAChR positive allosteric modulator, impairs memory when infused into the RSC, whereas in the HP, MLA and PNU display an opposite pharmacological profile. Moreover, co-infusion of MLA into both regions before training impaired memory expression, suggesting that the HP plays a predominant role in this intervention. Together, our results support a model in which α7nAChRs regulate aversive memory processing not only within the RSC but also through its functional interplay with the HP. This reveals a potential circuit-level mechanism for α7nAChR modulation and highlights their relevance as therapeutic targets to enhance cognitive function in the early stages of Alzheimer’s disease.