Hippocampal-Prefrontal θ Coupling Develops as Mice Become Proficient in Associative Odorant Discrimination Learning

Learning and memory requires coordinated activity between different regions of the brain. Here, we studied the interaction between infralimbic medial prefrontal cortex (mPFC) and hippocampal dorsal CA1 during associative odorant discrimination learning in the mouse. We found that as the animal learns to discriminate odorants in a go-no go task, the coupling of high-frequency neural oscillations to the phase of θ oscillations (θ-referenced phase-amplitude coupling or tPAC) changes in a manner that results in divergence between rewarded and unrewarded odorant-elicited changes in the θ phase-referenced power (tPRP) for β and γ oscillations. In addition, in the proficient animal there was a decrease in the coordinated oscillatory activity between CA1 and mPFC in the presence of the unrewarded odorant. Furthermore, the changes in tPAC resulted in a marked increase in the accuracy for decoding contextual odorant identity from tPRP when the animal became proficient. Finally, we studied the role of Ca²⁺/calmodulin-dependent protein kinase IIα (CaMKIIα), a protein involved in learning and memory, in oscillatory neural processing in this task. We find that the accuracy for decoding the contextual odorant identity from tPRP decreases in CaMKIIα knock-out mice and that this accuracy correlates with behavioral performance. These results implicate a role for tPAC and CaMKIIα in olfactory go-no go associative learning in the hippocampal-prefrontal circuit.