Neural mechanisms of cognitive generalization across species: From hippocampus to cortex

How do brains take what they have learned and apply it to new situations? This fundamental question sits at the core of cognitive generalization—a crucial ability that allows organisms to adapt to novel circumstances by drawing on prior experiences. While this mental flexibility enhances survival across species, the underlying neural mechanisms connecting different brain regions in rodents, primates, and humans remain poorly understood. Our review maps these neural pathways of generalization from hippocampus to cortex across the evolutionary spectrum. We show how hippocampal remapping and replay processes create abstract rules during generalization, with different hippocampal subregions handling distinct memory types. The prefrontal cortex emerges as essential for rule-based categorization across all species studied, while the orbitofrontal cortex drives value-based decision-making, and the posterior parietal cortex guides generalization through perceptual processing of past experiences. We explore the neural circuitry connecting these regions and examine how similar these brain structures and their associated behaviors are across species. Additionally, we discuss how disruptions to cognitive generalization manifest in various neurological conditions and their corresponding brain regions. This comprehensive analysis not only clarifies the neural foundations of cognitive generalization but also suggests promising directions for interventions targeting related neurological disorders.