The circuitry regulation of associative learning: dissociated and integrated function of the perirhinal cortex and...

The formation of associations, which involves binding disparate pieces of information, is fundamental to constructing episodic memory. This process primarily relies on the neural circuitry within the medial temporal lobe, specifically the hippocampal-parahippocampal network. Within this network, the perirhinal cortex (PER) and the hippocampus (HPC) are recognized as essential components for associative processing. While the traditional dual-pathway model depicts a hierarchically organized, sequential transmission of information along the medial temporal lobe, recent anatomical and functional studies reveal that the PER and HPC are embedded within a far more extensive and complex multi-pathway connectivity architecture. These connections enable parallel and dynamic interactions between PER, HPC, and other medial temporal lobe structures, supporting flexible modes of information processing and integration essential for associative learning. This review systematically re-evaluates the roles of the PER and HPC in associative learning. We begin by advancing the view that the PER acts not as a passive sensory gateway, but as an associative hub for multimodal association formation, whose special local inhibition provides the computational foundation for integrating complex information of both object features, and spatiotemporal context or affective valence. Building on this perspective, we then synthesize evidence on the dynamic interactions between the PER and HPC, encompassing findings from extensive anatomical and electrophysiological studies. Finally, we focus on the HPC, elucidating how it precisely coordinates information from the PER and other regions, with a particular emphasis on the critical regulatory roles played by inhibitory neurons in this integrative process. The reciprocal neuronal connections, coherent neuronal oscillatory activities and shared neuromodulation in the PER-HPC circuit facilitate the integration of associative learning.