Phase Matters: Responding to and Learning about Peripheral Stimuli Depends on Hippocampal ? Phase at Stimulus Onset

Hippocampal ? (3-12 Hz) oscillations are implicated in learning and memory, but their functional role remains unclear. We studied the effect of the phase of local ? oscillation on hippocampal responses to a neutral conditioned stimulus (CS) and subsequent learning of classical trace eyeblink conditioning in adult rabbits. High-amplitude, regular hippocampal ?-band responses (that predict good learning) were elicited by the CS when it was timed to commence at the fissure ? trough (Trough group). Regardless, learning in this group was not enhanced compared with a yoked control group, possibly due to a ceiling effect. However, when the CS was consistently presented to the peak of ? (Peak group), hippocampal ?-band responding was less organized and learning was retarded. In well-trained animals, the hippocampal ? phase at CS onset no longer affected performance of the learned response, suggesting a time-limited role for hippocampal processing in learning. To our knowledge, this is the first study to demonstrate that timing a peripheral stimulus to a specific phase of the hippocampal ? cycle produces robust effects on the synchronization of neural responses and affects learning at the behavioral level. Our results support the notion that the phase of spontaneous hippocampal ? oscillation is a means of regulating the processing of information in the brain to a behaviorally relevant degree.