Distinct Hippocampal-Prefrontal Coordination States Distinguish Between Successful and Unsuccessful Rule Learning

Why are some tasks harder to learn than others? What neural signatures distinguish successful from unsuccessful learning? Memory-guided behavior depends on interactions between the hippocampus (HPC) and prefrontal cortex (PFC). Theta-frequency activity is thought to support coordination between these regions and facilitate temporally coordinated neural activity during ongoing behavior. However, when individuals successfully learn one task but struggle to learn another despite similar experience, the neural mechanisms underlying distinct learning outcomes remain unclear. This dissertation investigated how hippocampal-prefrontal networks differ during successful and unsuccessful learning across multiple tasks. Using tetrode recordings of local field potentials (LFP) and single-unit activity from hippocampal dorsal CA1 and medial prefrontal cortex in freely behaving rats, I examined neural activity as animals performed two interleaved spatial alternation tasks with different learning outcomes. The findings revealed a dissociation between neural changes associated with repeated experience and those specifically associated with successful learning. Hippocampal spatial representations became increasingly stable, whereas hippocampal-prefrontal theta coherence strength progressively decreased with experience regardless of learning outcome, indicating that these changes primarily reflected increasing familiarity with the environment. In contrast, successful learning was characterized by increasingly consistent hippocampal-prefrontal theta coordination patterns, reduced hippocampal prospective coding, and stable prefrontal neural firing patterns that captured relationships among related action sequences. In addition, animals exhibiting similar behavioral patterns expressed similar hippocampal-prefrontal theta coordination patterns only during the restricted period of early rule acquisition, indicating a transient relationship between behavioral similarity and xiiihippocampal-prefrontal theta coordination during learning. Together, these findings provide a network-level framework for distinguishing neural changes associated with repeated experience from those associated with successful learning. They reveal that successful learning is characterized not by stronger overall hippocampal-prefrontal coordination, but by increasingly consistent spatiotemporal patterns of hippocampal-prefrontal coordination together with prefrontal representations that reflect relationships among related action sequences.