Cross-hemispheric gamma synchrony between prefrontal parvalbumin interneurons supports behavioral adaptation during rule shift learning.

Learning new associations that reappraise the behavioral significance of previously irrelevant cues requires gamma-frequency synchronization between parvalbumin interneurons in the left and right prefrontal cortex. Organisms must learn new strategies to adapt to changing environments. Activity in different neurons often exhibits synchronization that can dynamically enhance their communication and might create flexible brain states that facilitate changes in behavior. We studied the role of gamma-frequency (similar to 40 Hz) synchrony between prefrontal parvalbumin (PV) interneurons in mice learning multiple new cue-reward associations. Voltage indicators revealed cell-type-specific increases of cross-hemispheric gamma synchrony between PV interneurons when mice received feedback that previously learned associations were no longer valid. Disrupting this synchronization by delivering out-of-phase optogenetic stimulation caused mice to perseverate on outdated associations, an effect not reproduced by in-phase stimulation or out-of-phase stimulation at other frequencies. Gamma synchrony was specifically required when new associations used familiar cues that were previously irrelevant to behavioral outcomes, not when associations involved new cues or for reversing previously learned associations. Thus, gamma synchrony is indispensable for reappraising the behavioral salience of external cues.