Cortico-subcortical networks that determine behavioral memory renewal are redefined by noradrenergic neuromodulation

During spatial appetitive extinction learning (EL), rodents learn that previously rewarded behavior is no longer rewarded. Renewal of the extinguished behavior is enabled by re-exposure to the context in which rewarded learning occurred. When the renewal response (RR) is unrewarded, it is rapidly followed by response extinction (RE). Although the hippocampus is known to be engaged, whether this dynamic is supported by different brain networks is unclear. To clarify this, male rats engaged in context-dependent spatial memory acquisition, EL and RR testing in a T-Maze. Fluorescence in situ hybridization disambiguated somatic immediate early gene expression in neuronal somata engaged in RR or RE. Graph analysis revealed pronounced hippocampal connectivity with retrosplenial and prefrontal cortex (PFC) during initial RR. By contrast, RE was accompanied by a shift towards elevated coordinated activity within all hippocampal subfields. Given that β-adrenergic receptors (β-AR) regulate spatial memory, we activated β-AR to further scrutinize these network effects. This enhanced RR and prevented RE. Effects were associated with initially increased thalamic-hippocampus activity, followed by a decrease in hippocampal intraconnectivity and the predominance of network activity within PFC. Our findings highlight a critical hippocampal-cortical-thalamic network that underpins renewal behavior, with noradrenergic neuromodulation playing a pivotal role in governing this circuit's dynamics.